Cancer as a Parasitic Disease

Nooshin K Darvish Glioblastoma BorreliaCancer as a
Parasitic Disease

by Jeffrey Dach MD

Highlights from the 14th Annual International Integrative Oncology Conference in San Diego. April 16th, 2016

I was intrigued by a presentation by Dr Nooshin Darvish, of five cases of Glioblastoma Multiforme treated over ten years in her Holistique clinic located in Bellevue, Washington.   All five tumor biopsy samples stained positive for the spirochete parasite,Borrelia, the organism found in Lyme disease.(1)   The patient’s tumors regressed upon treatment for parasitic disease, and progressed when treatments were halted.  The pathology report by Alan MacDonald, M.D.,can be seen here:  Glioblastoma Five cases positive for Borrelia FISH Probes Alan MacDonald Darvish

Above Left Image courtesy of  Dr Nooshin K. Darvish, ND, FICT.

Borrelia SEM Lyme DiseaseBorrelia in Mantle Cell Lymphoma

This information was new to me, so I wondered if Borrelia had been associated with any other types of cancer.  A quick literature search answered the question. Dr Claudia Schöllkopf reported in Blood 2008 that patients who tested positive for Borrella antibodies had a 4 times higher risk of Mantle Cell lymphoma. (2)  Four years previously, in 2004, Borrelia organisms had been identified in two cases of nodal lymphoma.(3)  Left image: Worm-like structure are the Borellia parasite SEM scanning electron microscopy, courtesy of the Coltons Point Times.

Cancer as a Parasitic Disease is an Old Idea

Cancer as a form of parasitic disease is actually an old idea originally proposed by early microbiologists.  They considered the idea self evident from their microscopic observations of cancer cells.

William Russell Pathologist – 1890

Microsporidian_spore_wikimedia_colorOn December 3,1890 the Scottish pathologist William Russell reported a “cancer microbe” seen under his microscope inside cancer cells. His report in the Dec 18, 1890 British Medical Journal included detailed drawings describing parasitic spores within cancer cells.(24)  Over the next 120 years, Dr Russell’s hypothesis that cancer is a parasitic disease was picked up and championed by a long list of impressive scientists.  However all were labeled as medical heretics and lived out their careers in obscurity.  Left Image: Microsporidian spore courtesy of wikimedia. This organism is a spore-forming unicellular parasite, once though to be protozoans, now known to be fungi.

Cancer as a Placenta – Just Another Parasite ?

Placental_Cancer_Parasitic_Disease_Jeffrey Dach MDOne hundred years ago, a Scottish biologist John Beard noted cancer cell behavior was similar to behavior of the trophoblast cells of the placenta.  See my previous article on this.

In 2007 Dr Ferretti reported  on the striking similarity of proliferative, migratory and invasive features of both cancer and trophoblast cells, which use similar molecular cell pathways to achieve their goals.(48) Left Image: Schematic Drawing of Placenta (also called trophoblast) Courtesy of Cleveland Clinic.

Dr. Ferretti says:  “an overview of molecular circuitries shared by trophoblast and cancer cells reveals that the activation of the phosphatidylinositol 3′-kinase (PI3K)/AKT axis has recently emerged as a central feature of signalling pathways used by these cells to achieve their proliferative, migratory and invasive processes.”(48)

The placenta invades the surrounding uterine tissues and hijacks blood vessels to form its own blood supply.  The developing embryo is an implanted organism which, loosely speaking, can be described as “parasitic” by virtue of its reliance on the the mother’s blood supply for nutrition.   Is cancer a “placental cell”  gone haywire ?  A few of the speakers at the meeting raised this question.

More recently, authors have described cancer as its own parasitic species.(15)    The study of parasitic disease affords us an opportunity to understand cancer biology. (16-18)

Parasitic Disease in Animals

Above movie from (63) : Movie S1 from Ma M, Baumgartner M (2014). “Intracellular Theileria annulata Promote Invasive Cell Motility through Kinase Regulation of the Host Actin Cytoskeleton“. PLOS Pathogens.  Courtesy of Wikimedia Commons (63)

Parasitic protozoans may invade and hijack cell pathways to enhance survival.  In doing so, they may resemble cancer cells.  One such example is a tick borne parasitic infection called Theileria annulata, affecting South African cattle.  The invading parasite transforms the animal’s lymphocytes into lymphoma cells demonstrating all the hallmarks of cancer. (4)  Because of the similarity with cancer, this model has been extensively studied, hoping for clues leading to an understanding of cancer biology.(4-9)

Spirochete Parasite Transmitted by Ticks – Resembles Lymphoma

With an uncanny resemblance to the Borellia Lyme parasite in humans, Theileria is an intracellular parasites transmitted by ticks.   One species, T. parva, is highly pathogenic for cattle and causes fatal lymphoproliferative disease known as East Coast fever.  “Infected cells acquire a metastatic, cancer-like phenotype and are the primary cause of pathology”(9).  The parasite resides in the cell cytoplasm where it  inhibits host-cell apoptosis pathways to ensure self-survival. Theileria are intracellular protozoan parasites transmitted by ticks. The parasites synchronize their replication with that of the host cell so that daughter cells are also infected.  The parasite speeds up cell replication, benefiting its own survival.   Cancer cells share many of these same features, such as inhibition of apoptosis (immortalization) and  increased speed of replication.  The disease is reversible with anti-parasitic drug treatment with buparvaquone. (8)  Left upper image of Theileria courtesy of slide presentation at  RCVets.com.

Crytosporidium Mouse Model of Colon Cancer

Another animal model of parasitic disease inducing cancer is found in the laboratory of Dr Sadia Benamrouz who reported in 2014 that mice inoculated with the parasite, Crytosporidium,  quite unexpectedly develop colon cancer. (11)  They found histochemical evidence of upregulated WNT signalling pathways. This WNT pathway was discussed in a previous article. (11)

Parasitic disease such as Crypto and Toxo have increased prevalence in immunosuppressed cancer patients, so anti-parasitic chemo-prophylaxis  might be prudent in this group. (12-14)

Protozoan parasites belonging to the Apicomplexa phylumLeft image : Protozoan parasites belonging to the Apicomplexa phylum.  This phylum includes Babesia,  Thelieria and Malaria.  Image of Toxoplasmosis organism. Courtesy of Louis Kemp.

Anti-Parasitic Drugs are Anti-Cancer Drugs and Vice Versa

The Nobel prize in Medicine for 2015 was granted to three doctors for discovery of two anti-parasitic drugs, the anti-malarial drug Artemisinin (23), and the anti-parasitic drug Ivermectin.(19-22) Both drugs have been extensively studied for their potent anticancer effects as outlined in my previous article.

Pyrantel Pamoate (Parasitol) is an OTC pinword drug which synergizes the anti-cancer effect of Paclitaxel as reported by Dr Wu in 2012.

Pyrvinium Pamoate (Vanquin)  (25-29)

Pyrvinium is an old FDA approved drug for treatment of pinworm in the GI tract, a common parasitic infection in children. Available in Scandanavia, Germany , however not available in the US.  Oral preparations are not absorbed from the GI tract, making the drug a good choice in pregnant women.  In the US, pyrvinium has been replaced by mebenzadole and pyrantel.

Dr Liang Xu reports in the 2016 International Journal of Oncology , “The WNT pathway inhibitor pyrvinium pamoate inhibits the self-renewal and metastasis of breast cancer stem cells.” (25)  The drug has striking anti-cancer activity and is active against blast cell leukemia, lymphoma and breast cancer.(25-29)  Pyrvinium was patented for treatment of cancer in 2009.

Pyrvinium Inhibits NADH Fumarate Reductase

Not only does pyrvinium inhibit the WNT pathway, it also inhibits mitochondrial respiration in cancer cells.(59-60)  Dr Sakai, in a 2102 report, recognized that both parasites and cancer cells share the same hypoxic energy production fumarate reductase pathway. Pyrvinium targets this pathway in both parasites and cancer cell mitochondria, explaining the mechanism of pyrvinium anticancer activity.(59-60)

Praziquantel

The anti-schistosomal drug, Biltricide (praziquantel) was studied in 2012 by Dr Wu finding although not effective by itself, there was synergy with Paclitaxel, a commonly used chemotherapy drug.
pork tapeworm cysticercosis cancer as a parasitic diseaseNiclosamide – Niclide

Niclosamide, (tradename Niclocide), is FDA approved for the treatment of tapeworm infections (cestodes).  Niclosamide targets the Wnt/β-catenin pathway, serving as a potent anti-cancer drug.(30-33a)

Niclosanide in combination with cisplatin (chemotherapy) was found effective against ovarian cancer cells isolated from malignant ascites in 34 patients (31).  Niclosamide was also effective against colorectal cancer cell lines, Osteosarcoma and Glioblastoma cell lines. (30) Niclosamide was patented in 2012 for treatment of metastatic cancer.  Upper left image: SEM, head of tapeworm courtesy of Discover Magazine.

In A 2014 report in Cancer Letters, Dr Li says (61):

Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis.”(61)

In a 2012 report, Dr Pan says niclosamide is a potential Anti-cancer stem cell agent (62):

“Because niclosamide targets multiple signaling pathways (e.g., NF-κB, Wnt/β-catenin, and Notch), most of which are closely involved with cancer stem cells, it holds promise in eradicating cancer stem cells.”

Pork Tapeworm is endemic in developing countries with over 15% of household workers testing positive for antibodies to the parasite. (33b-d).  Even in people who avoid pork ingestion for religious/cultural reasons, nonetheless, tapeworm infection was found in orthodox Jewish communities transmitted from infected migrant workers from Latin America (33b-d)  Seizure disorder and characteristic cysts on brain CAT scan are typical findings in neurocysticercosis, found in 50% of migrant workers who test positive for anti-tapeworm antibodies.(33 b – d)

Niclosamide for treatment of Tapeworm is listed as an essential medicine by WHO, World health Organization.  Recommended adult dosage is 2 grams. “The tablets should be chewed thoroughly before swallowing and washed down with a little water. Adults: 2 g as a single dose.” (WHO)  For Dwarf tapeworm, dosage is 2 grams daily for seven days , and may be repeated a week later.

Nitazoxanide (NTZ) – Alinia

In 2013, Dr Fan-Minogue utilized the c-Myc sensor to establish a cell assay and optimized it to a high throughput-screening (HTS) format.  The authors screened about 5,000 existing bioactive compounds for potential activity as “c-Myc” inhibitors. “Among the most potent hits was nitazoxanide (NTZ), a human anti-protozoal drug.” Anticancer effects of NTZ was validated in various cancer cell lines in-vitro and in-vivo mouse xenograft models as well. (34)  Nitazoxanide  is available as Alinia tablets. (37)

Mebenzadole – The Anti-Parasitic Drug Vermox (49-55)

Upon screening 2,000 common drugs for anti-cancer activity against malignant melanoma, the anti-parasitic drug, mebenzadole (Vermox), was deemed the most promising agent. The authors state: “Mebendazole treatment induces apoptosis through the intrinsic and extrinsic (mitochondrial) pathways in melanoma cells but not in melanocytes… After treatment with 0.5 μmol/L mebendazole for 14 h, we observed overall microtubular network disarray” (49)

Recent studies show mebenzadole a promising agent for a number of cancers including medulloblastoma, a malignant brain tumor in children.  Animal xenograft studies show improved survival in mebenzadele treated animals.  Indeed, the authors suggested that Vincristine, the currently used chemotherapy drug, should be replaced by Mebenzadole which has better penetration across the blood brain barrier.  (54-55)

Conventional Chemotherapy Drugs As Anti-Parasitic Drugs

Not only do we have the surprising efficacy of anti-parasitic drugs against various cancers, we also have the reverse.  Conventional chemotherapy drugs have been repurposed as anti-parasitic drugs. (44)

Cancer as a Transmissible Parasite

Dr Claudio Murgio reported in 2004 on a type of transmissible cancer in dogs.  They studied genetic markers in the host dog and in the invading cancer cells, showing the cancer “has evolved into a transmissible parasite”, representing the oldest known somatic mammalian cell in continuous propagation.(38)

Indeed, we now have four examples of transmissible cancer, three in mammals and one in clams.(38-43):
1) Tasmanian Devil facial tumor disease
2) Canine transmissible venereal tumor
3) Hamster-induced transmissible sarcoma
4) Clam leukemia

Case Report of Cancer Arising From Tapeworm Infection

In 2015 Dr Atis Muehlenbachs reported a case of cancer as a transmissible parasite entitled “Malignant Transformation of Hymenolepis (TapeWorm) in a Human Host” , Dr Muehlenbachs described an unfortunate immunosupressed patient with enlarged lymph nodes invaded by cancer cells.  Genomic analysis of lymph node biopsy material revealed tapeworm DNA in the cancer cells, indicating the parasitic origin.  Perhaps the early 1890 microbiologist, William Russell, was right all along.

Conclusion: The link between cancer and parasitic disease is intriguing.  Animal models in which invading parasites transform normal cells into cancer cells has shed light on this connection.  The sheer fact that a wide array of anti-parasitic drugs serve as potent anti-cancer agents tends to support the hypothesis that cancer is a form of parasitic disease. 

This is part three of a series, for part one click here, for part two click here.

Articles With Related Interest:

Artemisinin Our Best Cancer Weapon

Targeting Cancer Stem Cells

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
954-792-4663

Parasites and Cancer is there a connection? Holtorf Medical Group
Thanks to Kent Holtorf MD for reprinting this article on their blog.

Links and References

Borrelia in Glioblastoma – Dr Nooshin K. Darvish, ND, FICT

1) https://www.drdarvish.com/glioblastoma-linked-to-lyme-disease

Glioblastoma Linked to Lyme Disease by: Nooshin K. Darvish, ND, FICT

In October 2015, Dr Darvish met Dr. Alan MacDonald, a retired neuropathologist. who agreed to analyze pathology slides of glioblastoma biopsies of five patients.  proving Dr. Darvish hypothesis and clinical evidence of ten years;  Using FISH (Flourescent In-Situ Hybridization), the DNA of Borrelia burgdorferi was found inside the cells of all five Glioblastoma brain tumors. On April 16th, 2016, Dr. Darvish presented her findings at the 14th Annual International Integrative Oncology Conference in San Diego.

———————————————-

Borrellia Associated with Cancer

2) http://www.bloodjournal.org/content/111/12/5524?sso-checked=true

Schöllkopf, Claudia, et al. “Borrelia infection and risk of non-Hodgkin lymphoma.” Blood 111.12 (2008): 5524-5529.

Reports of the presence of Borrelia burgdorferi DNA in malignant lymphomas have raised the hypothesis that infection with B burgdorferi may be causally related to non-Hodgkin lymphoma (NHL) development. We conducted a Danish-Swedish case-control study including 3055 NHL patients and 3187 population controls. History of tick bite or Borrelia infection was ascertained through structured telephone interviews and through enzyme-linked immunosorbent assay serum analyses for antibodies against B burgdorferi in a subset of 1579 patients and 1358 controls. Statistical associations with risk of NHL, including histologic subtypes, were assessed by logistic regression. Overall risk of NHL was not associated with self-reported history of tick bite (odds ratio [OR] = 1.0; 95% confidence interval: 0.9-1.1), Borrelia infection (OR = 1.3 [0.96-1.8]) or the presence of anti-Borrelia antibodies (OR = 1.3 [0.9-2.0]). However, in analyses of NHL subtypes, self-reported history of B burgdorferi infection (OR = 2.5 [1.2-5.1]) and seropositivity for anti-Borrelia antibodies (OR = 3.6 [1.8-7.4]) were both associated with risk of mantle cell lymphoma. Notably, this specific association was also observed in persons who did not recall Borrelia infection yet tested positive for anti-Borrelia antibodies (OR = 4.2 [2.0-8.9]). Our observations suggest a previously unreported association between B burgdorferi infection and risk of mantle cell lymphoma.

3) http://www.ncbi.nlm.nih.gov/pubmed/15370236/
Leuk Lymphoma. 2004 Aug;45(8):1721-3.
Demonstration of B. burgdorferi-DNA in two cases of nodal lymphoma.
Munksgaard L, Obitz ER, Goodlad JR, Davidson MM, Ho-Yen DO, Hamilton-Dutoit S, Hjalgrim H.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Theileria-transformed bovine leukocytes have cancer hallmarks

parasite causes lympho-proliferative —disease

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

full pdf
4) Tretina, Kyle, et al. “Theileria-transformed bovine leukocytes have cancer hallmarks.” Trends in parasitology 31.7 (2015): 306-314. Theileria transformed bovine leukocytes have cancer hallmarks_Kyle_Tretina_2015

5) http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103821
Wiens, Olga, et al. “Cell cycle-dependent phosphorylation of Theileria annulata schizont surface proteins.” PloS one 9.7 (2014): e103821.

6) http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066833
Kinnaird, Jane H., et al. “A bovine lymphosarcoma cell line infected with Theileria annulata exhibits an irreversible reconfiguration of host cell gene expression.” PloS one 8.6 (2013): e66833.

Theileria annulata, an intracellular parasite of bovine lymphoid cells, induces substantial phenotypic alterations to its host cell including continuous proliferation, cytoskeletal changes and resistance to apoptosis. While parasite induced modulation of host cell signal transduction pathways and NFκB activation are established, there remains considerable speculation on the complexities of the parasite directed control mechanisms that govern these radical changes to the host cell. Our objectives in this study were to provide a comprehensive analysis of the global changes to host cell gene expression with emphasis on those that result from direct intervention by the parasite. By using comparative microarray analysis of an uninfected bovine cell line and its Theileria infected counterpart, in conjunction with use of the specific parasitacidal agent, buparvaquone, we have identified a large number of host cell gene expression changes that result from parasite infection. Our results indicate that the viable parasite can irreversibly modify the transformed phenotype of a bovine cell line. Fifty percent of genes with altered expression failed to show a reversible response to parasite death, a possible contributing factor to initiation of host cell apoptosis. The genes that did show an early predicted response to loss of parasite viability highlighted a sub-group of genes that are likely to be under direct control by parasite infection. Network and pathway analysis demonstrated that this sub-group is significantly enriched for genes involved in regulation of chromatin modification and gene expression. The results provide evidence that the Theileria parasite has the regulatory capacity to generate widespread change to host cell gene expression in a complex and largely irreversible manner.

full free pdf

7) Hayashida, K., et al. “Comparative genome analysis of three eukaryotic parasites with differing abilities to transform leukocytes reveals key mediators of Theileria-induced leukocyte transformation.” mBio 3.5 (2011): e00204-12.

We sequenced the genome of Theileria orientalis, a tick-borne apicomplexan protozoan parasite of cattle. The focus of this study was a comparative genome analysis of T. orientalis relative to other highly pathogenic Theileria species, T. parva and T. annulata. T. parva and T. annulata induce transformation of infected cells of lymphocyte or macrophage/monocyte lineages; in contrast, T. orientalis does not induce uncontrolled proliferation of infected leukocytes and multiplies predominantly within infected erythrocytes. While synteny across homologous chromosomes of the three Theileria species was found to be well conserved overall, subtelomeric structures were found to differ substantially, as T. orientalis lacks the large tandemly arrayed subtelomere-encoded variable secreted protein-encoding gene family. Moreover, expansion of particular gene families by gene duplication was found in the genomes of the two transforming Theileria species, most notably, the TashAT/TpHN and Tar/Tpr gene families. Gene families that are present only in T. parva and T. annulata and not in T. orientalis, Babesia bovis, or Plasmodium were also identified. Identification of differences between the genome sequences of Theileria species with different abilities to transform and immortalize bovine leukocytes will provide insight into proteins and mechanisms that have evolved to induce and regulate this process. The T. orientalis genome database is available at http://totdb.czc.hokudai.ac.jp/.
Go to:

IMPORTANCE

Cancer-like growth of leukocytes infected with malignant Theileria parasites is a unique cellular event, as it involves the transformation and immortalization of one eukaryotic cell by another. In this study, we sequenced the whole genome of a nontransforming Theileria species, Theileria orientalis, and compared it to the published sequences representative of two malignant, transforming species, T. parva and T. annulata. The genome-wide comparison of these parasite species highlights significant genetic diversity that may be associated with evolution of the mechanism(s) deployed by an intracellular eukaryotic parasite to transform its host cell.

Theileria parva and Theileria annulata can be highly pathogenic to cattle and
Theileria lestoquardi can cause significant disease in sheep. These
three species are among the “transforming Theileria” species because
of their ability to transform and induce indefinite proliferation
of infected host leukocytes (1–4).

The resulting disease syndromes can be described as lymphoproliferative disorders, which often culminate in disorganization and destruction of the host lymphoid system.

full free pdf

8) Hayashida, Kyoko, et al. “MDM2 regulates a novel form of incomplete neoplastic transformation of Theileria parva infected lymphocytes.” Experimental and molecular pathology 94.1 (2013): 228-238.
Abstract

Our efforts are concerned with identifying features of incomplete malignant transformation caused by non viral pathogens. Theileria parva (T. parva) is a tick-transmitted protozoan parasite that can cause a fatal lymphoproliferative disease in cattle. The T. parva-infected lymphocytes display a transformed phenotype and proliferate in culture media like the other tumor cells, however those cells will return to normal after antiprotozoal treatment reflecting the incomplete nature of transformation. To identify signaling pathways involved in this form of transformation of T. parva-infected cells, we screened a library of anticancer compounds. Among these, TIBC, a specific inhibitor of MDM2, markedly inhibited proliferation of T. parva-infected lymphocytes and promoted apoptosis. Therefore we analyzed MDM2 function in T. parva-infected cells. Several T. parva-infected cell lines showed increased expression level of MDM2 with alternatively spliced isoforms compared to the lymphoma cells or ConA blasts. In addition, buparvaquone affected MDM2 expression in T. parva transformed cells. Moreover, p53 protein accumulation and function were impaired in T. parva-infected cells after cisplatin induced DNA damage despite the increased p53 transcription level. Finally, the treatment of T. parva-infected cells with boronic-chalcone derivatives TIBC restored p53 protein accumulation and induced Bax expression. These results suggest that the overexpression of MDM2 is closely linked to the inhibition of p53-dependent apoptosis of T. parva-infected lymphocytes. Aberrant expression of host lymphocyte MDM2 induced by cytoplasmic existence of T. parva, directly and/or indirectly, is associated with aspects of this type of transformation of T. parva-infected lymphocytes. This form of transformation shares features of oncogene induced malignant phenotype acquisition.

Members of the genus Theileria are intracellular apicomplexan protozoan parasites transmitted by ticks. Among several Theileria species, T. parva is highly pathogenic for cattle and cause fatal lymphoproliferative diseases known as East Coast fever (Brown et al., 1973; Irvin et al., 1975; Lawrence and Irvin, 1994). The schizont stage of T. parva resides within leukocytes and has direct contact with the host-cell cytoplasm and matrix. T. parva is among several parasites that inhibit host-cell apoptosis pathways to ensure their intracellular survival (Heussler et al., 2001b). The parasites have the unique ability to transform host lymphocytes and to synchronize their division with that of the host cell (Hulliger et al., 1964; von Schubert et al., 2010), ensuring that infection is maintained in daughter lymphocytes. Parasite multiplication is dependent on host-cell proliferation. The transformation and immortalization of T. parva-infected cells is very reminiscent of tumor cells, a major difference being that T. parva-induced transformation is reversible, as leukocytes return to a resting phenotype upon elimination of the parasite by the anti-parasitic agent buparvaquone. This suggests that transformation is not dependent on defined genomic changes in the host cell (Dobbelaere and Heussler, 1999). However, the underlying mechanisms by which T. parva-induces incomplete transformation have not been defined.

9) http://www.sciencedirect.com/science/article/pii/S1877959X16300152
Nene, Vishvanath, et al. “The biology of Theileria parva and control of East Coast fever–Current status and future trends.” Ticks and tick-borne diseases (2016).\

These infected cells acquire a metastatic, cancer-like phenotype and are the primary cause of pathology

10) D.A. Dobbelaere, V. Heussler.  Transformation of leukocytes by Theileria parva and T. annulata  Annu. Rev. Microbiol., 53 (1999), pp. 1–42

Theileria parva and T. annulata provide intriguing models for the study of parasite-host interactions. Both parasites possess the unique property of being able to transform the cells they infect; T. parva transforms T and B cells, whereas T. annulata affects B cells and monocytes/macrophages. Parasitized cells do not require antigenic stimulation or exogenous growth factors and acquire the ability to proliferate continuously. In vivo, parasitized cells undergo clonal expansion and infiltrate both lymphoid and non-lymphoid tissues of the infected host. Theileria-induced transformation is entirely reversible and is accompanied by the expression of a wide range of different lymphokines and cytokines, some of which may contribute to proliferation or may enhance spread and survival of the parasitized cell in the host. The presence of the parasite in the host-cell cytoplasm modulates the state of activation of a number of signal transduction pathways. This, in turn, leads to the activation of transcription factors, including nuclear factor-κB, which appear to be essential for the survival of Theileria- transformed T cells.

mouse model parasite crpto causes cancer with upregulation of WNT

11) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036476/  full free
Benamrouz, Sadia, et al.  “Cryptosporidium parvum-induced ileo-caecal adenocarcinoma and Wnt signaling in a mouse model.” Disease Models and Mechanisms 7.6 (2014): 693-700.

Unexpectedly, we observed that SCID mice that had been infected with C. parvum developed digestive adenocarcinoma

After infection of animals with C. parvum we demonstrated immunohistochemical abnormal localization of Wnt signaling pathway components and p53.

12) http://www.ncbi.nlm.nih.gov/pubmed/18985569
Turkiye Parazitol Derg. 2008;32(3):192-7.
[The prevalence of cryptosporidiosis in children who were diagnosed with leukemia and lymphoma]. [Article in Turkish] Tamer GS1, Balikçi E, Erbay A.

Cryptosporidium spp. is known to cause heavy diarrhea especially in immunosuppressed patients. In this study, eighty nine leukemia and lymphoma patients between the ages of 1 to 14 were studied for the prevalence of Cryptosporidiosis using both ELISA (Cryptosporidium Rida Screen, R-Biopharm, Germany) and the Kinyoun acid-fast staining method. These patients were sent to us by the Hematology-Oncology department where they were diagnosed with leukemia and lymphoma. Cryptosporidium spp. were detected in 11 patients (12.35%) with ELISA and in 7 patients (7.86%) with the Kinyoun acid fast stain. No cryptosporidiosis was detected in the control groups of 60 patients with neoplasia but without diarrhea. The distribution of Cryptosporidium among positive samples were 7 (14.8%) in patients who were diagnosed with ALL, 3 (10%) in patients who were diagnosed with KML, and 1 (8.3%) in patients who were diagnosed with solid tumors. Sixty-five patients (73.03%) had a fever, 43 patients (48.31%) were vomiting and 58 patients (65.16%) had stomach pain. Except for two, all the patients responded positively to paromomycin treatment. Those two patients responded positively to azitromycine treatment. We suggest that when considering cryptosporidiosis in children with cancer, the use of a more sensitive and specific method such as ELISA- in addition to the acid fast stain should be considered.

———————————————————————

Toxoplasmosis in Cancer samples by PCR

13) http://www.ncbi.nlm.nih.gov/pubmed/26683951
Medicine (Baltimore). 2015 Dec;94(50):e2274. doi: 10.1097/MD.0000000000002274.
The Seroprevalence of Toxoplasma gondii in Chinese Population With Cancer: A Systematic Review and Meta-analysis.
Jiang C1, Li Z, Chen P, Chen L.  1From the Department of Epidemiology and Health Statistics, School of Public Health, Central South University, Changsha, Hunan Province, China (CJ, ZL, LC); and Xiangya Medical School, Central South University, Changsha, Hunan Province, China (PC).

Toxoplasmosis is fatal in the immunocompromised individuals such as cancer patients with chemotherapy. Clinical toxoplasmosis in cancer patients is a great public health concern in China. We performed this meta-analysis to assess the seroprevalence and odds ratios (ORs) of Toxoplasma gondii in Chinese population with cancer compared with those without. A methodical literature search was conducted with the help of the PubMed, Web of Knowledge, Embase, Chinese Web of Knowledge, Wanfang, and Chongqing VIP database. Case-control studies published from their inception until April 2015, reporting the seroprevalence of T. gondii in Chinese population with cancer, were covered as well. The nonweighted prevalence, pooled random-effects estimates of ORs, and 95% confidence intervals (CIs) were all calculated. Nineteen studies including 4493 cases and 6797 controls were incorporated in the meta-analysis. The overall seroprevalence of T. gondii was higher in population with cancer compared with those without ((20.59% vs 6.31%, P?<?0.001; OR 3.90, 95% CI 3.00-5.07). The OR of T. gondii in cancer patients is further subgrouped according to publication year, sample size, and diagnostic methods. The pooled OR estimates were 4.80 (95% CI 2.57-8.99) from 1991 to 1999, 4.96 (95% CI 3.03-8.12) during 2000 to 2005, and 2.94 (95% CI 2.46-3.50) during 2006 to 2015. The pooled OR estimates were 6.16 (95% CI 3.87-9.78) when the sample size was below 400, 5.37 (95% CI 3.84-7.53) when the sample size was between 400 and 500, and 2.58 (95% CI 2.17-3.07) when the sample size was above 500. The pooled OR estimates were 5.50 (95% CI 3.98-7.62) by using indirect hemagglutination assay method, and 3.15 (95% CI 2.67-3.72) by using enzyme-linked immunosorbent assay method. The meta-analysis study found Chinese population with cancer had higher seroprevalence rates of T. gondii compared with those without.

14) http://www.ncbi.nlm.nih.gov/pubmed/25641340
Cancer Lett. 2015 Apr 10;359(2):307-13. Toxoplasma gondii infection in cancer patients: prevalence, risk factors, genotypes and association with clinical diagnosis. Cong W1, Liu GH2, Meng QF3, Dong W4, Qin SY1, Zhang FK2, Zhang XY5, Wang XY6, Qian AD7, Zhu XQ8.

Prevalence of human infection with Toxoplasma gondii has been increasing in China due to the increasing number of cats. However, little is known of the epidemiology of T. gondii infection in different cancer patient groups. Thus, a case-control study of 900 cancer patients and 900 controls was conducted to detect anti-T. gondii antibodies by ELISA in China. Genomic DNA was extracted from the diseased tissues of 510 patients and the T. gondii B1 gene was amplified using a semi-nested PCR. DNA samples giving positive B1 amplification were then genetically characterized using multi-locus PCR-RFLP. The prevalence of anti-T. gondii IgG in cancer patients (35.56%) was significantly higher than that in controls (17.44%). The highest T. gondii seroprevalence was detected in lung cancer patients (60.94%), followed by cervical cancer patients (50%), brain cancer patients (42.31%) and endometrial cancer patients (41.67%). Exposure with soil and consumption of raw/undercooked meat were significantly associated with T. gondii infection in cancer patients. Three T. gondii genotypes (ToxoDB#9, ToxoDB#10 and Type I variant) were identified. In conclusion, T. gondii infection is a severe problem in cancer patients and it is imperative that improved integrated measures should be conducted to prevent and control T. gondii infection in cancer patients.

—–

Cancer as a Parasite Species

15) http://www.ncbi.nlm.nih.gov/pubmed/16023792
Med Hypotheses. 2005;65(5):846-50.
Clinically significant cancer evolves from transient mutated and/or aneuploid neoplasia by cell fusion to form unstable syncytia that give rise to ecologically viable parasite species.  Parris GE1.

Following the idea of Duesberg and Rasnick (Cell Motil Cytoskeleton 2000; 47:81-107) that cancer is a separate species of organism, the ecology of cancer as a parasite is examined. The most important ecological feature of cancer is its ability to evolve. The mutation hypothesis and the “unstable genome” hypothesis of cancer evolution are considered but neither of these current hypotheses is believed to adequately explain how cancer successfully evolves. In particular, either of these processes alone should lead to extinction of the cell line before a clinically significant neoplasm is achieved. Moreover, the term “unstable genome” probably should be replaced by “labile genome” because cancer genomes must be stable enough to reproduce themselves through many generations if the clone is to expand. The key step in productive evolution of undetectable neoplasia into clinically significant cancer is hypothesized to be sex-like resorting of chromosomes from different cells (e.g., normal and abnormal cells). The sex-like process begins with cell fusion to form a syncytium, which may be stable (producing multinucleated giant cells seen in many tumors) or which may undergo “mitotic catastrophe” to produce polyploidy cells. The nuclei of polyploid cells may undergo a process called “neosis” in which they form buds and undergo karyokinesis followed by cytokinesis to yield karyoplasts (small cells with little cytoplasm) that found new cancer clone lines. Although both mutations and unstable (aneuploid) genomes are seen as dead ends in cancer evolution (i.e., using only these modes of genome modification, cancers would not likely advance to clinical significance before becoming extinct), they each produce transient genetic material, which can be incorporated into stable genomes with aggressive (i.e., ecologically fit) phenotypes by cell fusion. It is proposed that inhibition of cell fusion (or other steps in this sex-like process) concurrent with classical chemotherapy might prevent evolution of the clones and recurrence of the cancer. Similarly, active suppression of viruses or other conditions that catalyze cell fusion should also slow down evolution of cancer clones.

2016

16) Ujvari, Beata, et al. “Cancer and life-history traits: lessons from host–parasite interactions.” Parasitology 143.05 (2016): 533-541.

Cancer is a Metabolic Parasite  2013

17) http://www.ncbi.nlm.nih.gov/pubmed/23615669
Bull Cancer. 2013 May;100(5):427-33. doi: 10.1684/bdc.2013.1742.
[The cancer tumor: a metabolic parasite?]. [Article in French] Icard P1, Lincet H.

Cancer cells activate glycolysis, glutaminolysis and ß-oxidation to promote their biosynthesis. The low activity of pyruvate kinase, reexpressed in its embryonic isoform PKM2, generates a bottleneck at the end of glycolysis, which reorients glucose catabolism towards formation of molecules implied in numerous synthesis: ribose for nucleic acids, glycerol for lipid synthesis, etc. However, a part of glucose is transformed in pyruvate, which also comes from aminoacids catabolism. Due to the inhibition of pyruvate dehydrogenase, pyruvate is preferentially transformed into lactate, either in the presence of oxygen (Warburg effect). Lactate dehydrogenase reaction furnishes lactic acid, which acidifies the tumoral microenvironment, a process which favors the cellular growth and regenerates NAD(+), a crucial cofactor for the functioning of various metabolic pathways (glycolysis, DNA synthesis and repair…). Cancer cells consume a lot of glutamine, which replenish Krebs cycle (coupled with ATP production), and/or furnishes aspartate for nucleotides synthesis. This particular metabolism is sustained by activation of oncogenes (Myc, AKT, etc.) and suppressors inactivation (P53, PTEN…). Like a parasite, cells draw on reserves of the host to supply their own biosynthesis, while they secrete waste products (NO, polyamines, ammonia, lactate…) that promote cellular growth. A “symbiotic” cooperation could be established between tumor cells themselves, and/or with environmental cells, to maximize ATP production in relation with resources and oxygen concentration.

18) Oliveira, Guilherme. “Cancer and parasitic infections: similarities and opportunities for the development of new control tools.” Revista da Sociedade Brasileira de Medicina Tropical 47.1 (2014): 1-2.

Anti-Parasitic Drugs

Ivermectin

19) Melotti, Alice, et al. “The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer.” EMBO molecular medicine (2014): e201404084.

20) Draganov, Dobrin, et al. “Modulation of P2X4/P2X7/pannexin-1 sensitivity to extracellular ATP via ivermectin induces a non-apoptotic and inflammatory form of cancer cell death.” Scientific reports 5 (2015).

21) Drinyaev, Victor A., et al. “Antitumor effect of avermectins.” European journal of pharmacology 501.1 (2004): 19-23.

22) Sharmeen, Sumaiya, et al. “The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells.” Blood 116.18 (2010): 3593-3603.

23) Das A K. Anticancer effect of antimalarial artemisinin compounds. Ann Med Health Sci Res [serial online] 2015 [cited 2016 Feb 13];5:93-102.

24) Russell, William. “An address on a characteristic organism of cancer.” British medical journal 2.1563 (1890): 1356. Russell William Characteristic Organism of Cancer British Medical Journal 1890.

Pyrvinium Pamoate

25) Xu, Liang, et al. “WNT pathway inhibitor pyrvinium pamoate inhibits the self-renewal and metastasis of breast cancer stem cells.” International journal of oncology 48.3 (2016): 1175-1186.  Int J Oncol. 2016 Mar;48(3):1175-86. doi: 10.3892/ijo.2016.3337. Epub 2016 Jan 13.

Acquisition of chemoresistance and metastatic phenotype are the major causes of breast cancer treatment failure and cancer-related mortality. Recently, a plethora of experimental and clinical studies points toward a central role of cancer stem cells (CSCs) in the chemoresistance and metastasis. In the present study, we demonstrated that pyrvinium pamoate (PP), an anthelmintic drug, inhibited proliferation of different subtypes of breast cancer cells (luminal: MCF-7, claudin-low: MDA-MB‑231, basal-like: MDA-MB‑468 and Her-2 enriched: SkBr-3) as a novel WNT pathway inhibitor. Additionally, PP was also shown to inhibit self-renewal of breast cancer stem cells (BCSCs) and decrease both CD44+CD24-/low and ALDH-positive BCSCs content in a panel of breast cancer cell lines. Besides, the metastatic potential and expression of EMT markers (such as N-cadherin, vimentin, Snail) were also found suppressed by PP. By using a xenograft model, we next tested the efficacy of PP on tumorigenicity of MDA-MB‑231, one of the most aggressive breast cancer cell lines, and we observed PP significantly delayed tumor growth in vivo. Moreover, in-depth analysis revealed that PP caused inhibition of WNT pathway activity and stemness regulator expression including NANOG, SOX2 and OCT4, which were inherently upregulated in the BCSCs as compared with the bulk of cells within the tumor. Collectively, our findings provide direct evidence for PP serving as a promising high-yield agent targeting BCSCs and cancer heterogeneity. Therefore, strategies combining PP with standard chemotherapy drugs which fail to eliminate the BCSCs hold promise to overcome BCSCs associated treatment resistance and achieve a better therapeutic outcome.

26) Xiao, Meifang, et al. “Pyrvinium selectively induces apoptosis of lymphoma cells through impairing mitochondrial functions and JAK2/STAT5.” Biochemical and biophysical research communications 469.3 (2016): 716-722.

Targeting mitochondrial respiration has emerged as an attractive therapeutic strategy in blood cancer due to their unique metabolic dependencies. In this study, we show that pyrvinium, a FDA-approved anthelmintic drug, selectively targets lymphoma T-cells though inhibition of mitochondrial functions and JAK2/STAT5. Pyrvinium induces apoptosis of malignant T-cell line Jurkat and primary T-cells from lymphoma patients while sparing T-cells from healthy donors. Increased level of active caspase-3 and decreased levels of Bcl-2 and Mcl-1 were also observed in Jurkat and lymphoma T-cells but not normal T-cells treated with pyrvinium. In addition, pyrvinium impairs mitochondrial functions by inhibit mitochondrial respiration, suppressing mitochondrial respiratory complex I activity, increasing ROS and decreasing ATP levels. However, the effects of pyrvinium were abolished in mitochondrial respiration-deficient Jurkat ρ(0) cells, confirming that pyrvinium acts on lymphoma T-cells via targeting mitochondrial respiration. We further show that lymphoma T-cells derived from patients depend more on mitochondrial respiration than normal T-cells, and this explains the selective toxicity of pyrvinium in lymphoma versus normal T-cells. Finally, we demonstrate that pyrvinium also suppresses JAK2/STAT5 signaling pathway in Jurkat cells. Our study suggests that pyrvinium is a useful addition to T-cell lymphoma treatment, and emphasizes the potential therapeutic value of the differences in the mitochondrial characteristics between malignant and normal T-cells in blood cancer.

27) http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071508
The Antihelmintic Drug Pyrvinium Pamoate Targets Aggressive Breast Cancer
Wei Xu, PLOS     Published: August 27, 2013

28) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462317/
Front Oncol. 2012; 2: 137. Reprofiling a classical anthelmintic, pyrvinium pamoate, as an anti-cancer drug targeting mitochondrial respiration .  Isao Ishii,1,* Yasuo Harada,2 and Tadashi Kasahara1

full pdf

29) Xiang, Wei, et al. “Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration.” Oncotarget 6.32 (2015): 33769-33780.

While pyrvinium has been shown to inhibit the Wnt/β-catenin signalling pathway via activation of casein kinase 1α , we find its activity in CML is not dependent on this pathway. Instead, we show that pyrvinium localizes to mitochondria and induces apoptosis by inhibiting mitochondrial respiration.

——————————————–;”;l

Niclosamide (trade name Niclocide[1]) is a teniacide in the anthelmintic family especially effective against cestodes that infect humans and many other animals. It is a salicylanilide compound (5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydrobenzamide) also used as a piscicide.

niclosamide

30) Osada, Takuya, et al. “Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.” Cancer research 71.12 (2011): 4172-4182.

Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC. Cancer Res; 71(12); 4172–82. ©2011 AACR.

31) Arend, Rebecca C., et al. “Inhibition of Wnt/β-catenin pathway by niclosamide: A therapeutic target for ovarian cancer.” Gynecologic oncology 134.1 (2014): 112-120.

Objective. The Wnt/β-catenin pathway is known to regulate cellular proliferation and plays a role in chemoresistance. Niclosamide, an FDA approved salicyclamide derivative used for the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. Therefore, the objective of this study was to investigate niclosamide as a potential therapeutic agent for ovarian cancer.

Methods. Tumor cells isolated from 34 patients’ ascites with primary ovarian cancer were treated with niclosamide (0.1 to 5 μM) ± carboplatin (5 to 150 μM). Cell viability was assessed using the ATP-lite assay. LRP6, Axin 2, Cyclin D1, survivin and cytosolic free β-catenin levels were determined using Western blot analysis. Tumorspheres were treated, and Wnt transcriptional activity was measured by the TOPflash reporter assay. ALDH and CD133 were analyzed by Flow cytometry and IHC. ALDH1A1 and LRP6 were analyzed by IHC in solid tumor and in ascites before and after treatment with niclosamide.

Results. Combination treatment produced increased cytotoxicity compared to single agent treatment in 32/34 patient samples. Western blot analysis showed a decrease in Wnt/β-catenin pathway proteins and the expression of target genes. A significant reduction of Wnt/β-catenin signaling was confirmed by TOPflash assay. There was increased staining of ALDH1A1 and LRP6 in ascites compared to solid tumor which decreased after treatment.

Conclusion. This study demonstrates that niclosamide is a potent Wnt/β-catenin inhibitor. Targeting the Wnt/β-catenin pathway led to decreased cellular proliferation and increased cell death. These findings warrant further research of this drug and other niclosamide analogs as a treatment option for ovarian cancer.

32) Chen, W., M. Chen, and L. S. Barak. “Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach.” American journal of physiology. Gastrointestinal and liver physiology 299.2 (2010): G293.

33) Am J Physiol Gastrointest Liver Physiol. 2010 Aug;299(2):G293-300.
Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach. Chen W1, Chen M, Barak LS.

Wnt proteins play major roles in development and differentiation, and abnormalities in their regulation are believed to contribute to the formation of many cancers, including colorectal malignancies. As a result, there has been an interest in identifying small molecule inhibitors of Wnt signaling as tool compounds for research or as precursors to new generations of anticancer drugs. Advancements in robotic technology along with reductions in the costs of equipment, chemical libraries, and information handling have made high-throughput drug discovery programs possible in an academic setting. In this minireview we discuss the most plausible protein targets for inhibiting Wnt signaling in colon cancer therapy, list small molecule Wnt inhibitors that have been identified through recent drug discovery efforts, and provide our laboratory’s strategy for identifying novel Wnt signaling antagonists using high-throughput screening. In particular, we summarize the results of a screen of over 1,200 drug and druglike compounds we recently completed in which niclosamide was identified as a Wnt pathway antagonist.

anti-cancer effect of nitazoxanide (NTZ), a thiazolide for treating human protozoal infections.

33a) CDC Parasites Treatment – Hymenolepiasis (also known as Hymenolepis nana infection)
Praziquantel, adults and children, 25mg/kg in a single-dose therapy.
Alternatives:

Niclosamide*: adults, 2 gm in a single dose for 7 days; children 11-34 kg, 1 gm in a single dose on day 1 then 500 mg per day orally for 6 days; children > 34 kg, 1.5 gm in a single dose on day 1 then 1 gm per day orally for 6 days.

Nitazoxanide: adults, 500 mg orally twice daily for 3 days; children aged 12-47 months, 100 mg orally twice daily for 3 days; children 4-11 years, 200 mg orally twice daily for 3 days.

TapeWorm in Orthodox Jewish COmmunity from Migrant Household Workers

33b) PM Schantz et al. (1992) Neurocysticercosis in an Orthodox Jewish community in New York City. N Engl J Med 327: 692–695

33c) AC Moore et al. (1995) Seroprevalence of Cysticercosis in an Orthodox Jewish Community. Am J Trop Med Hyg 53(5):439-442 3.

33d) BN Huisa et al. (2005) Taeniasis and cysticercosis in housemaids working in affluent neighborhoods in Lima, Peru. Am J Trop Med Hyg. 73(3): 496–500

Nitozoxanide

34) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772774/
Fan-Minogue, Hua, et al. “A c-Myc activation sensor-based high throughput drug screening identifies an anti-neoplastic effect of Nitazoxanide.” Molecular cancer therapeutics 12.9 (2013): 1896.

nitazoxanide (NTZ), a thiazolide for treating human protozoal infections.
Validation of NTZ in different cancer cell lines revealed a high potency for c-Myc inhibition with IC50 ranging between 10 – 500nM. Oral administration of NTZ in breast cancer xenograft mouse models significantly suppressed tumor growth by inhibition of c-Myc and induction of apoptosis. These findings suggest a potential of NTZ to be repurposed as a new anti-tumor agent for inhibition of c-Myc associated neoplasia

In this study, we utilized the c-Myc sensor to establish a cell assay and optimized it to a high throughput-screening (HTS) format. Using this assay in a quantitative HTS (qHTS) platform, we screened about 5,000 existing bioactive compounds for potential c-Myc inhibitors. Among the most potent hits was nitazoxanide (NTZ), a human anti-protozoal drug. We further validated its inhibitory effect on c-Myc in different tumor cell lines and the efficacy of tumor inhibition in mouse xenograft models.

full free pdf

35) Di Santo, Nicola, and Jessie Ehrisman. “Research perspective: potential role of nitazoxanide in ovarian cancer treatment. Old drug, new purpose?.” Cancers 5.3 (2013): 1163-1176.

nitazoxanide (NTZ)—of the thiazolide family—is a safe and inexpensive broad-spectrum, FDA approved, drug. NTZ is traditionally utilized for the treatment of anaerobic intestinal parasites Giardia lamblia and Cryptosporidium parvum, and has also been found efficacious in the treatment of other anaerobic bacteria and parasites residing in the human bowel [13].

36) http://www.sciencedirect.com/science/article/pii/S0027510714001006
Di Santo, Nicola, and Jessie Ehrisman. “A functional perspective of nitazoxanide as a potential anticancer drug.” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 768 (2014): 16-21.

Cancer is a group of diseases characterized by uncontrolled cell proliferation, evasion of cell death and the ability to invade and disrupt vital tissue function. The classic model of carcinogenesis describes successive clonal expansion driven by the accumulation of mutations that eliminate restraints on proliferation and cell survival. It has been proposed that during cancer’s development, the loose-knit colonies of only partially differentiated cells display some unicellular/prokaryotic behavior reminiscent of robust ancient life forms. The seeming “regression” of cancer cells involves changes within metabolic machinery and survival strategies. This atavist change in physiology enables cancer cells to behave as selfish “neo-endo-parasites” that exploit the tumor stromal cells in order to extract nutrients from the surrounding microenvironment. In this framework, it is conceivable that anti-parasitic compounds might serve as promising anticancer drugs. Nitazoxanide (NTZ), a thiazolide compound, has shown antimicrobial properties against anaerobic bacteria, as well as against helminths and protozoa. NTZ has also been successfully used to promote Hepatitis C virus (HCV) elimination by improving interferon signaling and promoting autophagy. More compelling however are the potential anti-cancer properties that have been observed. NTZ seems to be able to interfere with crucial metabolic and pro-death signaling such as drug detoxification, unfolded protein response (UPR), autophagy, anti-cytokine activities and c-Myc inhibition. In this article, we review the ability of NTZ to interfere with integrated survival mechanisms of cancer cells and propose that this compound might be a potent addition to the current chemotherapeutic strategy against cancer.
Keywords

Autophagy; Protein disulfide isomerase; Microenvironment; Nitazoxanide; c-Myc; Glutathione S-transferase; Interleukin 6


37) Alinia Tablets are round, yellow, film-coated tablets debossed with ALINIA on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide. The tablets are packaged in HDPE bottles of 60 tablets and blister cards of 6 tablets.

Bottles of 60 NDC 67546-111-11
Boxes of 3 blister cards NDC 67546-111-32
(Alinia 3-Day Therapy Packs™)

CLINICAL STUDIES
Diarrhea caused by Giardia lamblia in adults and adolescents 12 years of age or older:
In a double-blind, controlled study (Study 1) conducted in Peru and Egypt in adults and adolescents with diarrhea caused by Giardia lamblia, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days.
————-
Diarrhea caused by Cryptosporidium parvum in adults and adolescents 12 years of age or older: In a double-blind, controlled study conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days.

———————————————————————————————-
Transmissible Tumors  2016

38) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593932/  full free
Murgia, Claudio, et al. “Clonal Origin and Evolution of a Transmissible Cancer.” Cell 126.3 (2006): 477.

The transmissible agent causing canine transmissible venereal tumor (CTVT) is thought to be the tumor cell itself. To test this hypothesis, we analyzed genetic markers including major histocompatibility (MHC) genes, microsatellites, and mitochondrial DNA (mtDNA) in naturally occurring tumors and matched blood samples. In each case, the tumor is genetically distinct from its host. Moreover, tumors collected from 40 dogs in 5 continents are derived from a single neoplastic clone that has diverged into two subclades. Phylogenetic analyses indicate that CTVT most likely originated from a wolf or an East Asian breed of dog between 200 and 2500 years ago. Although CTVT is highly aneuploid, it has a remarkably stable genotype. During progressive growth, CTVT downmodulates MHC antigen expression. Our findings have implications for understanding genome instability in cancer, natural transplantation of allografts, and the capacity of a somatic cell to evolve into a transmissible parasite.We provide conclusive evidence that a cancer cell has evolved into a transmissible parasite, which represents the oldest known somatic mammalian cell in continuous propagation.

39) http://www.cell.com/trends/genetics/fulltext/S0168-9525%2815%2900187-0  free full text

Trends Genet. 2016 Jan;32(1):1-15.  Transmissible Tumors: Breaking the Cancer Paradigm.  Ostrander EA1, Davis BW2, Ostrander GK3.
Author information      1National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Building 50 Room 5351, Bethesda MD 20892, USA. Electronic address: eostrand@mail.nih.gov.
2National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Building 50 Room 5351, Bethesda MD 20892, USA.
3Department of Biomedical Science, 600W College Ave, College of Medicine, Florida State University, Tallahassee, Tallahassee, FL 32306, USA.

Abstract

Transmissible tumors are those that have transcended the bounds of their incipient hosts by evolving the ability to infect another individual through direct transfer of cancer cells, thus becoming parasitic cancer clones. Coitus, biting, and scratching are transfer mechanisms for the two primary species studied, the domestic dog (Canis lupus familiaris) and the Tasmanian devil (Sarcophilus harrisii). Canine transmissible venereal tumors (CTVT) are likely thousands of years old, and have successfully travelled from host to host around the world, while the Tasmanian devil facial tumor disease (DFTD) is much younger and geographically localized. The dog tumor is not necessarily lethal, while the devil tumor has driven the population to near extinction. Transmissible tumors are uniform in that they have complex immunologic profiles, which allow them to escape immune detection by their hosts, sometimes for long periods of time. In this review, we explore how transmissible tumors in CTVT, DFTD, and as well as the soft-shell clam and Syrian hamster, can advance studies of tumor biology.

leukemia in clams  full free pdf

40) Metzger, Michael J., et al. “Horizontal transmission of clonal cancer cells causes leukemia in soft-shell clams.” Cell 161.2 (2015): 255-263.

Here, we first extend the observation that neoplastic cells
contain common Steamer integration sites that are not
present in normal animals or in normal tissues of diseased animals.
These results have two possible explanations: either
Steamer retrotransposons exhibit unprecedented selectivity for
specific integration sites in these multiple neoplasms, or these
neoplasms did not arise independently but are descendants of a
primordial leukemic cell carrying these common Steamer integrations,
similar to the contagious cancers observed in dogs
and Tasmanian devils. We therefore analyzed mitochondrial
DNA (mtDNA) sequences and polymorphic microsatellite repeat
loci and found that the genotypes of the neoplastic cells do not
match those of their hosts. Furthermore, all neoplastic genotypes
are nearly identical to each other, strongly arguing that
soft-shell clam leukemia across the Atlantic coast is horizontally
transmitted as a contagious cancer cell derived from a single
clonal origin.

Clam leukemia genotypes are distinct from their hosts and
nearly identical to each other
The transmissible cancer clone likely arose in a single
individual
Clam leukemia is transmitted horizontally between animals
as contagious cancer cells
Contagious cancer cell transmission may be widespread in
the marine environment

transmissible canine cancer

41) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918581/   full free
Murchison, Elizabeth P., et al. “Transmissible dog cancer genome reveals the origin and history of an ancient cell lineage.” Science 343.6169 (2014): 437-440.

Canine transmissible venereal tumor (CTVT) is the oldest known somatic cell lineage. It is a transmissible cancer that propagates naturally in dogs. We sequenced the genomes of two CTVT tumors and found that CTVT has acquired 1.9 million somatic substitution mutations and bears evidence of exposure to ultraviolet light. CTVT is remarkably stable and lacks subclonal heterogeneity despite thousands of rearrangements, copy number changes and retrotransposon insertions. More than 10,000 genes carry non-synonymous variants and 646 genes have been lost. CTVT first arose in a dog with low genomic heterozygosity that may have lived approximately 11,000 years ago. The cancer spawned by this individual dispersed across continents approximately 500 years ago. Our results provide a genetic identikit of an ancient dog and demonstrate the robustness of mammalian somatic cells to survive for millennia despite a massive mutation burden.

42) http://genome.cshlp.org/content/25/11/1646.full
Decker, Brennan, et al. “Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor.” Genome research 25.11 (2015): 1646-1655.

As an infectious allograft, it has adopted strategies similar to intercellular obligate parasites (Wijayawardena et al. 2013), even subsuming mitochondria from its host (Rebbeck et al. 2011).

full free

43) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982769/
Murchison, Elizabeth P., et al. “The Tasmanian devil transcriptome reveals Schwann cell origins of a clonally transmissible cancer.” Science 327.5961 (2010): 84-87.

The Tasmanian devil, a marsupial carnivore, is endangered because of the emergence of a transmissible cancer known as devil facial tumor disease (DFTD). This fatal cancer is clonally derived and is an allograft transmitted between devils by biting. We performed a large-scale genetic analysis of DFTD with microsatellite genotyping, a mitochondrial genome analysis, and deep sequencing of the DFTD transcriptome and microRNAs. These studies confirm that DFTD is a monophyletic clonally transmissible tumor and suggest that the disease is of Schwann cell origin. On the basis of these results, we have generated a diagnostic marker for DFTD and identify a suite of genes relevant to DFTD pathology and transmission. We provide a genomic data set for the Tasmanian devil that is applicable to cancer diagnosis, disease evolution, and conservation biology.

44) Klinkert, M-Q., and V. Heussler. “The use of anticancer drugs in antiparasitic chemotherapy.” Mini reviews in medicinal chemistry 6.2 (2006): 131-143.

full free pdf
45) Muehlenbachs, Atis, et al. “Malignant Transformation of Hymenolepis nana in a Human Host.” New England Journal of Medicine 373.19 (2015): 1845-1852. Malignant Transformation of Hymenolepis nana in a Human Host Tapeworm NEJM Muehlenbachs 2015

The patient received three doses of albendazole as empirical treatment
However, the efficacy of albendazole against clonal proliferations of tapeworm stem cells as opposed to whole organisms is questionable. Typical gastrointestinal H. nana infection is treated with praziquantel or nitazoxanide, and albendazole is the drug of choice for tissue-invasion stages of larval cestodes.

full free pdf
46) Ujvari, Beata, Robert A. Gatenby, and Frédéric Thomas. “The evolutionary ecology of transmissible cancers.” Infection, Genetics and Evolution 39 (2016): 293-303. Evolutionary ecology of transmissible cancers Beata Ujvari 2016

full pdf
47) Tissot, Tazzio, et al. “Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.” BioEssays (2016). Host manipulation by cancer cells BioEssays 2016 Tissot Tazzio

There are four examples of transmissible cancers: three mammalian (Devil facial tumor disease (DFTD), canine transmissible venereal tumor (CTVT), hamster-induced transmissible sarcoma) and one invertebrate (clam leukemia, CL) transmissible cancer cell lines have so far been identified.

full free pdf
48) Ferretti, C., et al. “Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts.” Human reproduction update 13.2 (2007): 121-141. Molecular circuits shared by placental and cancer cells trophoblasts Ferretti Human reproduction 2007

Trophoblast research over the past decades has underlined the striking similarities between the proliferative, migratory and invasive properties of placental cells and those of cancer cells. This review recapitulates the numerous key molecules, proto-oncogenes, growth factors, receptors, enzymes, hormones, peptides and tumour-associated antigens (TAAs) expressed by both trophoblastic and cancer cells in an attempt to evaluate the genes and proteins forming molecular circuits and regulating the similar behaviours of these cells. Among the autocrine and paracrine loops that might be involved in the strong proliferative capacity of trophoblastic and cancer cells, epidermal growth factor (EGF)/EGF receptor (EGFR), hepatocyte growth factor (HGF)/HGF receptor (HGFR) (Met) and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) loops may play a predominant role. Similar mechanisms of migration and invasion displayed by trophoblastic and malignant cells comprise alterations in the adhesion molecule phenotype, including the increased expression of alpha1beta1 and alphavbeta3 integrin receptors, whereas another critical molecular event is the down-regulation of the cell adhesion molecule E-cadherin. Among proteases that may play an active role in the invasive capacities of these cells, accumulating evidence suggests that matrix metalloproteinase-9 (MMP-9) expression/activation is a prerequisite. Finally, an overview of molecular circuitries shared by trophoblast and cancer cells reveals that the activation of the phosphatidylinositol 3′-kinase (PI3K)/AKT axis has recently emerged as a central feature of signalling pathways used by these cells to achieve their proliferative, migratory and invasive processes.

Anti-Parasitic Drug Vermox  (mebendazole)

49) mebendazole metastatic colon cancer Nygren Acta Oncologica 2014
Nygren, Peter, and Rolf Larsson. “Drug repositioning from bench to bedside: Tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer.” Acta Oncologica 53.3 (2014): 427-428.

50) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/
Pantziarka, Pan et al. “Repurposing Drugs in Oncology (ReDO)—mebendazole as an Anti-Cancer Agent.” ecancermedicalscience 8 (2014): 443. PMC. Web. 13 Jan. 2015.

51)http://mcr.aacrjournals.org/content/6/8/1308.full 
Doudican, Nicole, et al. “Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells.” Molecular Cancer Research 6.8 (2008): 1308-1315.

52)  http://neuro-oncology.oxfordjournals.org/content/early/2011/07/14/neuonc.nor077.full   Bai, Ren-Yuan, et al. “Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme.” Neuro-oncology (2011): nor077.

53)Mebendazole metastatic adrenocortical carcinoma Dobrosotskaya Endocrine practice 2011 Dobrosotskaya, I. Y., et al. “Mebendazole monotherapy and long-term disease control in metastatic adrenocortical carcinoma.” Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 17.3 (2011): e59.

54) Gamble, Alex, et al. “ATPS-83REPURPOSING MEBENDAZOLE AS A REPLACEMENT FOR VINCRISTINE FOR THE TREATMENT OF BRAIN TUMORS.” Neuro-Oncology 17.suppl 5 (2015): v36-v36.
We found that mebendazole showed a 61% increase in animal survival time, whereas vincristine failed to show any efficacy. However, we did observe significant neuropathy (as measured by sensory allodynia) induced by mebendazole treatment, similar to that caused by vincristine. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.

55) Bodhinayake, Imithri, Marc Symons, and John A. Boockvar. “Repurposing Mebendazole for the Treatment of Medulloblastoma.” Neurosurgery 76.2 (2015): N15-N16. Repurposing Mebendazole Treatment Medulloblastoma Neurosurgery Bodhinayake 2015

Treatment of Parasitic Diease with Anti-Parasitic Drugs

56) Albrich, Jennifer. “Helminths and anthelmintics.” Professional Nursing Today 13.5 (2009): 8-10. Helminths and anthelmintics Professional Nursing Today Albrich 2009

57) Kucik, Corry Jeb, Gary L. Martin, and Brett V. Sortor. “Common intestinal parasites.” American family physician 69.5 (2004). full pdf available

58) Woodhall, Dana, et al. “Neglected parasitic infections: what every family physician needs to know.” Am Fam Physician 89.10 (2014): 803-11. Neglected parasitic infections Am Fam Physician 2014 Dana Woodhall


Pyrvinium

free pdf

59) Sakai, Chika, et al. “Mitochondrial fumarate reductase as a target of chemotherapy: from parasites to cancer cells.” Biochimica et Biophysica Acta (BBA)-General Subjects 1820.5 (2012): 643-651.  Mitochondrial fumarate reductase as a target of chemotherapy from parasites to cancer cells BBA Sakai C 2012

A leading drug in the treatment of Ascaris infection is Ivermectin, a semi-synthetic derivatie of the natural product of a streptomyces species; Avermectin B1a.
Pyrvinium

60) Tomitsuka, Eriko, Kiyoshi Kita, and Hiroyasu Esumi. “An anticancer agent, pyrvinium pamoate inhibits the NADH–fumarate reductase system—a unique mitochondrial energy metabolism in tumour microenvironments.” Journal of biochemistry 152.2 (2012): 171-183. Anticancer pyrvinium pamoate inhibits NADH Fumarate System Tomitsuka EJ Biochem 2012

PP inhibited the hypoxic electron transport chain ETC, NADHFR system in both parasitic and mammalian mitochondria, showing that the NADHFR system is active in both parasitic and mammalian mitochondria.
key effects of PP such as its anticancer and selective cytotoxic effects, may arise through the inhibition of the NADHFR system. Therefore, the
NADHFR system is a good target for anticancer therapy.

Niclosamide

61) Li, Yonghe, et al. “Multi-targeted therapy of cancer by niclosamide: A new application for an old drug.” Cancer letters 349.1 (2014): 8-14.

62)  Pan, Jing-Xuan, Ke Ding, and Cheng-Yan Wang. “Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells.” Chinese journal of cancer 31.4 (2012): 178.

Because niclosamide targets multiple signaling pathways (e.g., NF-κB, Wnt/β-catenin, and Notch), most of which are closely involved with cancer stem cells, it holds promise in eradicating cancer stem cells.

63)  Ma, Min, and Martin Baumgartner. “Intracellular Theileria annulata promote invasive cell motility through kinase regulation of the host actin cytoskeleton.” PLoS Pathog 10.3 (2014): e1004003.

The intracellular, protozoan Theileria species parasites are the only eukaryotes known to transform another eukaryotic cell. One consequence of this parasite-dependent transformation is the acquisition of motile and invasive properties of parasitized cells in vitro and their metastatic dissemination in the animal, which causes East Coast Fever (T. parva) or Tropical Theileriosis (T. annulata). These motile and invasive properties of infected host cells are enabled by parasite-dependent, poorly understood F-actin dynamics that control host cell membrane protrusions. Herein, we dissected functional and structural alterations that cause acquired motility and invasiveness of T. annulata-infected cells, to understand the molecular basis driving cell dissemination in Tropical Theileriosis. We found that chronic induction of TNFα by the parasite contributes to motility and invasiveness of parasitized host cells. We show that TNFα does so by specifically targeting expression and function of the host proto-oncogenic ser/thr kinase MAP4K4. Blocking either TNFα secretion or MAP4K4 expression dampens the formation of polar, F-actin-rich invasion structures and impairs cell motility in 3D. We identified the F-actin binding ERM family proteins as MAP4K4 downstream effectors in this process because TNFα-induced ERM activation and cell invasiveness are sensitive to MAP4K4 depletion. MAP4K4 expression in infected cells is induced by TNFα-JNK signalling and maintained by the inhibition of translational repression, whereby both effects are parasite dependent. Thus, parasite-induced TNFα promotes invasive motility of infected cells through the activation of MAP4K4, an evolutionary conserved kinase that controls cytoskeleton dynamics and cell motility. Hence, MAP4K4 couples inflammatory signaling to morphodynamic processes and cell motility, a process exploited by the intracellular Theileria parasite to increase its host cell’s dissemination capabilities.

64) Mebendazole
the-over-the-counter-drug-mebendazole-acts-like-chemotherapy-but-with-virtually-no-side-effects


https://youtu.be/_Ii87PYaRCA
Parasite in Cancer  – Medical Education
http://www.nejm.org/gastroenterology?topic=11&q=*&subtopic=11_3

———————————————————————-

Cell Fusion  —- Nice Image !!!!!!!!!

first evidence of cell fusion in melanoma mets from allogeneic transplant pt

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694119/  full free
Lazova, Rossitza, et al. “A Melanoma Brain Metastasis with a Donor-Patient Hybrid Genome following Bone Marrow Transplantation: First Evidence for Fusion in Human Cancer.” PLoS ONE 8.6 (2013).

Pawelek, John M. “Fusion of bone marrow-derived cells with cancer cells: metastasis as a secondary disease in cancer.” Chin J Cancer 33 (2014): 133-139.
——————————————————————————

ful free pdf
Kloc, M., X. C. Li, and R. M. Ghobrial. “Are Macrophages Responsible for Cancer Metastasis.” J Immuno Biol 1.103 (2016): 2.
Recently,  Shabo et al. [23] showed that breast and colorectal cancer cells express macrophage-specific antigen CD163 and proved experimentally that
cancer cells acquire this trait by direct fusion with macrophages.

—————————–

full pdf free

Sainz, Bruno, et al. “Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies.” Mediators of Inflammation 2016 (2016).

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Cell Fusion

full free pdf

http://www.ncbi.nlm.nih.gov/pubmed/23237551
Crit Rev Oncog. 2013;18(1-2):19-42.
Cell fusion in tumor development: accelerated genetic evolution.
Harkness T1, Weaver BA, Alexander CM, Ogle BM.

The majority of human tumor cells have highly aberrant karyotypes, typically ascribed to errors during tumor cell division, potentially linked to a failure of DNA repair, or telomeric insufficiency. Here we discuss another option, that of cell fusion which can lead to the re-assortment of chromosomes during post-fusion mitosis. The observation of hyperdiploid cells has a long history in cancer genetics, but the concept of cell fusion has been difficult to test in practice. Here, we examine the role of cell fusion during normal development, and relate that to potential cellular fusion partners for primary tumor cells. In particular, we describe the potential for stromal partner fusion during metastatic mobilization. The evidence for genetic and cytoplasmic diversity in heterotypic fusion partners is described, together with the new tools available to help the evaluation of this process as a tumor driver.

the first clue that fusion may be involved in oncogenesis is that tetraploidy is common in premalignant lesions and often gives way to aneuploidy in later stages.25, 91-92 The best-studied example of this phenomenon is probably Barrett’s esophagus, a premalignant condition in which tetraploid cells are predictive of progression into both aneuploidy and cancer.93-94 Tetraploidy has also been detected in premalignant lesions in cervical cancer,95 head and neck squamous cell carcinoma,96 and Kaposi sarcoma;97 however, it is unknown whether tetraploid cells in these lesions progress to malignancy. Direct evidence for carcinogenesis as a result of tetraploidy comes from a 2005 study in which p53-/- tetraploid cells were derived through chemically inhibiting cytokinesis.98 These p53-/- tetraploid cells formed tumors when implanted subcutaneously in nude mice while isogenic p53-/- diploid cells did not. Karyotyping of resultant tumors showed they were near-tetraploid with numerous structural rearrangements. The observations that a majority of cancer cell lines in the NCI-60 drug screening panel99 and elsewhere100-102 are hyperdiploid and that karyotypes are generally preserved between cell lines and the primary tumors they were derived from100, 103 suggest that the progression from tetraploidy to aneuploidy may be common in many cancers in vivo.
It has been reported that there exists a p53-

Call Fusion 2015

http://www.ncbi.nlm.nih.gov/pubmed/26066710
Zhou, Xiaofeng, et al. “Cell fusion connects oncogenesis with tumor evolution.” The American journal of pathology 185.7 (2015): 2049-2060.

Cell fusion likely drives tumor evolution by undermining chromosomal and DNA stability and/or by generating phenotypic diversity; however, whether a cell fusion event can initiate malignancy and direct tumor evolution is unknown. We report that a fusion event involving normal, nontransformed, cytogenetically stable epithelial cells can initiate chromosomal instability, DNA damage, cell transformation, and malignancy. Clonal analysis of fused cells reveals that the karyotypic and phenotypic potential of tumors formed by cell fusion is established immediately or within a few cell divisions after the fusion event, without further ongoing genetic and phenotypic plasticity, and that subsequent evolution of such tumors reflects selection from the initial diverse population rather than ongoing plasticity of the progeny. Thus, one cell fusion event can both initiate malignancy and fuel evolution of the tumor that ensues.

Cell Fusion 2015

http://www.mdpi.com/1422-0067/16/12/26240/htm  full free
Dittmar, Thomas, and Kurt S. Zänker. “Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells.” International journal of molecular sciences 16.12 (2015): 30362-30381.

————————–Cryptosporidosis and colon cancer

full free pdf
Tin, Sim Sai, and Viroj Wiwanitkit. “Cryptosporidiosis and Colorectal Cancer.” Annals of Colorectal Research 3.3 (2015).

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
very improtant

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036476/
Benamrouz, Sadia, et al. “Cryptosporidium parvum-induced ileo-caecal adenocarcinoma and Wnt signaling in a mouse model.” Disease Models and Mechanisms 7.6 (2014): 693-700.

After infection of animals with C. parvum we demonstrated immunohistochemical abnormal localization of Wnt signaling pathway components and p53.

NICE image of Crytoporidium SEM Stanford Medical

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005429
full free
Sateriale, Adam, and Boris Striepen. “Beg, Borrow and Steal: Three Aspects of Horizontal Gene Transfer in the Protozoan Parasite, Cryptosporidium parvum.” PLoS Pathog 12.3 (2016): e1005429.

LDH , anaerobic metabolism, evades immune system

————————————————————-
Horizontal Gene Transfer in mammals/humans

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358723/
Genome Biol. 2015 Mar 13;16:50. doi: 10.1186/s13059-015-0607-3.
Expression of multiple horizontally acquired genes is a hallmark of both vertebrate and invertebrate genomes.
Crisp A, Boschetti C, Perry M, Tunnacliffe A, Micklem G.
Abstract
BACKGROUND:

A fundamental concept in biology is that heritable material, DNA, is passed from parent to offspring, a process called vertical gene transfer. An alternative mechanism of gene acquisition is through horizontal gene transfer (HGT), which involves movement of genetic material between different species. HGT is well-known in single-celled organisms such as bacteria, but its existence in higher organisms, including animals, is less well established, and is controversial in humans.
RESULTS:

We have taken advantage of the recent availability of a sufficient number of high-quality genomes and associated transcriptomes to carry out a detailed examination of HGT in 26 animal species (10 primates, 12 flies and four nematodes) and a simplified analysis in a further 14 vertebrates. Genome-wide comparative and phylogenetic analyses show that HGT in animals typically gives rise to tens or hundreds of active ‘foreign’ genes, largely concerned with metabolism. Our analyses suggest that while fruit flies and nematodes have continued to acquire foreign genes throughout their evolution, humans and other primates have gained relatively few since their common ancestor. We also resolve the controversy surrounding previous evidence of HGT in humans and provide at least 33 new examples of horizontally acquired genes.
CONCLUSIONS:

We argue that HGT has occurred, and continues to occur, on a previously unsuspected scale in metazoans and is likely to have contributed to biochemical diversification during animal evolution.

HGT occurs at low, but appreciable, levels across all the animal species we examined; it has occurred over time and is still occurring; it mainly originates from bacteria and protists; and the genes concerned frequently code for enzyme activities. Interestingly, overall levels of HGT do not appear to be conspicuously different in vertebrates and invertebrates.

————————–

cell fusion hybrid hypothesis

http://www.mdpi.com/1422-0067/16/12/26240/htm
Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells
Thomas Dittmar * and Kurt S. Zänker
Institute of Immunology & Experimental Oncology, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke, Witten 58453, Germany

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
cell fusion and malignancy

http://www.ncbi.nlm.nih.gov/pubmed/26066710
Zhou, Xiaofeng, et al. “Cell fusion connects oncogenesis with tumor evolution.” The American journal of pathology 185.7 (2015): 2049-2060.
Cell fusion likely drives tumor evolution by undermining chromosomal and DNA stability and/or by generating phenotypic diversity; however, whether a cell fusion event can initiate malignancy and direct tumor evolution is unknown. We report that a fusion event involving normal, nontransformed, cytogenetically stable epithelial cells can initiate chromosomal instability, DNA damage, cell transformation, and malignancy. Clonal analysis of fused cells reveals that the karyotypic and phenotypic potential of tumors formed by cell fusion is established immediately or within a few cell divisions after the fusion event, without further ongoing genetic and phenotypic plasticity, and that subsequent evolution of such tumors reflects selection from the initial diverse population rather than ongoing plasticity of the progeny. Thus, one cell fusion event can both initiate malignancy and fuel evolution of the tumor that ensues.

———————-

call fusion

pdf of first page only

Coleman, William B. “Genomic Catastrophe and Neoplastic Transformation.” The American journal of pathology 185.7 (2015): 1846-1849.

The study by
Zhou et al4 used an innovative experimental design that
enabled examination of oncogenic molecular events
occurring early after fusion of normal (nonneoplastic) rat
intestinal crypt epithelial (IEC-6) cells. The objective of
this study was to determine whether a cell fusion event
involving normal cells will precipitate molecular alterations
that drive neoplastic transformation and tumorigenesis.
Cell fusion has been suggested as a possible
initiating event in cancer development based on several
observations: i) cell fusion events can be detected in
existing cancers,5 ii) cell fusion is associated with genomic
instability, which could drive neoplastic transformation,6
and iii) cell fusion may account for neoplastic transformation
among nonproliferative differentiated cell
types.7

Experimental Model of Cell Fusion
Zhou et al4 used rat IEC-6 cells8 which have a stable diploid
karyotype, lack cellular characteristics of neoplasticallytransformed
cells in vitro, and fail to form tumors in animals
after repeated passaging in cell culture. IEC-6 cells
were fluorescently labeled using either green (CSFE) or red
(SNARF-1) dyes, mixed, cell fusion was mediated with
50% polyethylene glycol (PEG), and the resulting cell
population was subjected to fluorescence-activated cell
sorting (FACS) to identify fused and non-fused cells. Fused
cells were larger in size and exhibited dual fluorescent
signal, whereas non-fused cells were of normal size and
displayed only one fluorescent marker.4 Fused cells were
sorted and clonal populations were established and subsequently
characterized for growth properties in vitro, markers
of DNA damage, and tumorigenic potential in vivo.4

—————————–

tetraploidy in Mantle cell Blastoid

http://www.bloodjournal.org/content/89/4/1421?sso-checked=true
wnt      German Ott, Jörg Kalla, M. Michaela Ott, Birgit Schryen, Tiemo Katzenberger, Justus G. Müller, and Hans K. Müller-Hermelink 1 From the Department of Pathology, University of Würzburg, Würzburg, Germany.

However, the most interesting finding was a striking tendency of blastoid MCL subtypes to harbor chromosome numbers in the tetraploid range (36% of lymphoblastoid and 80% of pleomorphic types v 8% of common variants, P < .001)

—————————————-

full free pdf

http://www.ncbi.nlm.nih.gov/pubmed/23237551
Crit Rev Oncog. 2013;18(1-2):19-42.
Cell fusion in tumor development: accelerated genetic evolution.
Harkness T1, Weaver BA, Alexander CM, Ogle BM.
Author information    1Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.

The majority of human tumor cells have highly aberrant karyotypes, typically ascribed to errors during tumor cell division, potentially linked to a failure of DNA repair, or telomeric insufficiency. Here we discuss another option, that of cell fusion which can lead to the re-assortment of chromosomes during post-fusion mitosis. The observation of hyperdiploid cells has a long history in cancer genetics, but the concept of cell fusion has been difficult to test in practice. Here, we examine the role of cell fusion during normal development, and relate that to potential cellular fusion partners for primary tumor cells. In particular, we describe the potential for stromal partner fusion during metastatic mobilization. The evidence for genetic and cytoplasmic diversity in heterotypic fusion partners is described, together with the new tools available to help the evaluation of this process as a tumor driver.

the first clue that fusion may be involved in oncogenesis is that tetraploidy is common in premalignant lesions and often gives way to aneuploidy in later stages.25, 91-92 The best-studied example of this phenomenon is probably Barrett’s esophagus, a premalignant condition in which tetraploid cells are predictive of progression into both aneuploidy and cancer.93-94 Tetraploidy has also been detected in premalignant lesions in cervical cancer,95 head and neck squamous cell carcinoma,96 and Kaposi sarcoma;97

The observations that a majority of cancer cell lines in the NCI-60 drug screening panel99 and elsewhere100-102 are hyperdiploid and that karyotypes are generally preserved between cell lines and the primary tumors they were derived from100, 103 suggest that the progression from tetraploidy to aneuploidy may be common in many cancers in vivo

—————–
WNT

Watanabe, Kazuhide, and Xing Dai. “Winning WNT: race to Wnt signaling inhibitors.” Proceedings of the National Academy of Sciences 108.15 (2011): 5929-5930.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423515/
Wnt blockers inhibit the proliferation of lung cancer stem cells
Xueyan Zhang,1,* Yuqing Lou,1,* Xiaoxuan Zheng,1 Huimin Wang,1 Jiayuan Sun,1 Qianggang Dong,2 and Baohui Han1
Author information ► Copyright and License information ►

_____________________________

C-Myc

http://mcb.asm.org/content/19/1/1.short

Dang, Chi V. “c-Myc target genes involved in cell growth, apoptosis, and metabolism.” Molecular and cellular biology 19.1 (1999): 1-11.

Recent evidence suggests that activation of c-myc gene expression is central to signal transduction through the adenomatous polyposis coli (APC) tumor suppressor protein which negatively regulates β-catenin (Fig. 1) (80). β-Catenin is a coactivator for the transcription factor Tcf, which is able to directly activate c-mycexpression, so that when APC is inactivated, activation of β-catenin results. The activities of human transforming proteins BCR-ABL (2,158) and TEL-PDGFR (31) and proto-oncogenes c-src (13) and Wnt (33) have been shown to depend on the c-myc gene (Fig. 1). In retrospect, the emergence of c-myc as a central oncogenic switch in human cancers might have been predicted by the ability of the oncogenic retroviral v-myc gene to cause the rapid development of a variety of tumors in infected chickens

full pdf
Wnt/b-Catenin Signaling Pathway Upregulates c-Myc Expression to Promote Cell Proliferation of P19
Teratocarcinoma Cells SHUAI ZHANG, YI LI, YULING WU, KUN SHI, LUJUN BING, AND JING HAO*
Department of Histology and Embryology, School of Medicine, Shandong University,
Jinan 250012, People’s Republic of China

ABSTRACT
Aberrant activation of the Wnt/b-catenin signaling pathway is a common
event in human tumor progression. Wnt signaling has also been implicated
in maintaining a variety of adult and embryonic stem cells by
imposing a restraint to differentiation. To understand the function and
mechanism of Wnt/b-catenin signaling on the pathogenesis of teratocarcinoma,
we used the mouse teratocarcinoma P19 cell line as a model in vitro.
Gsk3b specific inhibitor (SB216763) was used to activate Wnt/b-catenin signaling.
All trans-retinoic acid (RA) was used to induce P19 cell differentiation.
At different culture times, gene expression was examined by
immunofluorescence staining, quantitative real-time PCR, and Westernblotting;
BrdU incorporation assays were performed to measure P19 cell
proliferation. Small interference RNA technology was used to downregulate
c-myc expression. The results showed that SB216763 induced the nuclear
translocation of b-catenin, upregulated the expression of c-myc and pluripotency
related genes, oct4, sox2 and nanog, and blocked cell differentiation
induced by all trans-RA. The proliferation of P19 cells was significantly
enhanced by SB216763, as well as c-myc overexpression. C-myc downregulation
inhibited P19 cell proliferation caused by activation of Wnt/b-catenin
signaling and induced P19 cell differentiation. In conclusion, activation of
the Wnt/b-catenin pathway could promote the proliferation and inhibit the
differentiation of mouse teratocarcinoma cells by upregulation of c-myc
expression. Anat Rec, 295:2104–2113, 2012. VC 2012 Wiley Periodicals, Inc.

http://asheducationbook.hematologylibrary.org/content/2013/1/575.full
The main cell functions and pathways under control of MYC are cell proliferation and growth, DNA replication, protein biosynthesis, and regulation of metabolism and energy. MYC promotes the transition from the G0/1 phase to the S phase, activating directly and indirectly the expression of CCND2 and CDKs and down-regulating cell cycle inhibitors.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
bacterial animal lateral gene transfer and cancer
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003877
Robinson, Kelly M., Karsten B. Sieber, and Julie C. Dunning Hotopp. “A review of bacteria-animal lateral gene transfer may inform our understanding of diseases like cancer.” PLoS Genet 9.10 (2013): e1003877.

Hypothesis 1: Bacterial DNA Integration into Somatic Cells Could Induce Oncogenic Mutations

http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003107
Riley, David R., et al. “Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples.” PLoS Comput Biol 9.6 (2013): e1003107.

We detected the integration of bacterial DNA in the human genome more readily in tumors than normal samples. In particular, extensive amounts of DNA with similarity to Acinetobacter DNA were fused to human mitochondrial DNA in acute myeloid leukemia samples. We also identified specific integrations of DNA with similarity to Pseudomonas DNA near the untranslated regulatory regions of four proto-oncogenes. This supports our hypothesis that bacterial integrations occur in the human somatic genome that may potentially play a role in carcinogenesis.

—–

https://clincancerres.aacrjournals.org/content/20/20/5207.full
Zucca, Emanuele, et al. “Emerging role of infectious etiologies in the pathogenesis of marginal zone B-cell lymphomas.” Clinical Cancer Research 20.20 (2014): 5207-5216.

http://www.ncbi.nlm.nih.gov/pubmed/25975444
Curr Treat Options Oncol. 2015 Jun;16(6):28. doi: 10.1007/s11864-015-0344-6.
The role of infectious agents, antibiotics, and antiviral therapy in the treatment of extranodal marginal zone lymphoma and other low-grade lymphomas.
Foster LH1, Portell CA.

There is strong evidence to corroborate the association with Helicobacter pylori (Hp) to gastric extranodal marginal zone lymphoma (ENMZL) and hepatitis C virus (HCV) to splenic/nodal marginal zone lymphoma. Koch’s postulates generally hold for these two associations and eradication of the infectious agent is well supported. Hp eradication (HPE) is recommended as front-line therapy for early stage gastric ENMZL regardless of Hp status. Complete response (CR) rate for Hp-negative patients is not as high as for Hp-positive patients; however, the benign nature of HPE and high rates of salvage allow this strategy to be safe while sparing some Hp-negative patients from systemic therapy or radiation. Similarly for HCV-seropositive patients, treatment with antivirals should be strongly considered as first-line for those who do not require immediate cytoreductive therapy or at some point even after completing chemoimmunotherapy. The controversy regarding the role for antibiotics is greatest for primary ocular adnexal lymphoma (POAL). Considering the low incidence of Chlamydia psittaci (Cp) infection with OAL and the challenges to reliably identifying Cp, we typically do not consider doxycycline in POAL treatment. Involved-field radiotherapy (IFRT) remains the treatment of choice for most with unilateral POAL. However, if reliable detection of Cp is available and Cp is identified, patients with unilateral low tumor stage POAL who do not require immediate radiotherapy could be considered for doxycycline as front-line treatment. Other infectious associations to indolent lymphomas have been made, including Borrelia borgdorferi (Bb) in cutaneous lymphoma and Campylobacter in immunoproliferative small intestinal disease (IPSID), but these associations are not as strong and primary treatment targeting the infectious agents is not recommended.

http://journals.lww.com/jcge/Citation/2016/05000/Successful_Treatment_of_HCV_associated_B_Cell.20.aspx
de Clerck, Frederik, et al. “Successful Treatment of HCV-associated B-Cell Non-Hodgkin Lymphomas With Direct-acting Antiviral Agents.” Journal of clinical gastroenterology 50.5 (2016): 438.

http://www.ncbi.nlm.nih.gov/pubmed/26773441
Raderer, M., B. Kiesewetter, and A. J. Ferreri. “Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).” CA: a cancer journal for clinicians (2015).

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

————————————————-

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809900/

Crosier, M. D., and M. D. Phuc LeHoang. “Detection of Helicobacter pylori and Chlamydia pneumoniae genes in primary orbital lymphoma.” Trans Am Ophthalmol Soc 104 (2006): 62-70.

H pylori or C pneumoniae genomic fingerprints were detected in two of seven primary orbital MALT lymphomas. These findings provide evidence for a possible involvement of particular infectious microorganisms such as H pylori and Chlamydia in primary orbital lymphoma. These different microorganisms may play similar roles in the etiology of orbital MALT lymphomas from different geographic regions. Antibiotic therapy could be considered for orbital MALT lymphomas associated with positive infection.\

Prostate Cancer Caused by Parasite

Detection of Protozoan DNA Sequences In Prostate Cancer
By Stephen E Fry, M.D.
Backed by Ryan Lower and David Stifter
We have hypothesized that human prostatic carcinoma could be triggered by an unrecognized protozoal infection.

Parasites and Cancer is there a connection? Holtorf Medical Group
Thanks to Kent Holtorf MD for reprinting my article on their blog.
Wu, Zhen Hua, et al. “Praziquantel Synergistically Enhances Paclitaxel Efficacy to Inhibit Cancer Cell Growth.” PLoS ONE 7.12 (2012).

=================================
Pyrvinium (Vanquin)

Thorne, Curtis A et al. “Small-Molecule Inhibition of Wnt Signaling through Activation of Casein Kinase 1α.” Nature chemical biology 6.11 (2010): 829–836. PMC. Web. 21 Aug. 2016.
FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC50 of ~10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.
Pyrvinium Pamoate anti cancer drug
Xu, Wei, et al. “The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer.” PloS one 8.8 (2013): e71508.
Xiang, Wei, et al. “Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration.” Oncotarget 6.32 (2015): 33769.
Xiao, Meifang, et al. “Pyrvinium selectively induces apoptosis of lymphoma cells through impairing mitochondrial functions and JAK2/STAT5.” Biochemical and biophysical research communications 469.3 (2016): 716-722.

link to this page http://wp.me/p3gFbV-3wM

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com
http://www.drdach.com
http://www.naturalmedicine101.com
http://www.bioidenticalhormones101.com

http://www.truemedmd.com

Disclaimer click here: http://www.drdach.com/wst_page20.html

The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.

Copyright (c) 2016 Jeffrey Dach MD All Rights Reserved. This article may be reproduced on the internet without permission, provided there is a link to this page and proper credit is given.

FAIR USE NOTICE: This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of issues of significance. We believe this constitutes a ‘fair use’ of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.

Serving Areas of: Hollywood, Aventura, Miami, Fort Lauderdale, Pembroke Pines, Miramar, Davie, Coral Springs, Cooper City, Sunshine Ranches, Hallandale, Surfside, Miami Beach, Sunny Isles, Normandy Isles, Coral Gables, Hialeah, Golden Beach ,Kendall,sunrise, coral springs, parkland,pompano, boca raton, palm beach, weston, dania beach, tamarac, oakland park, boynton beach, delray,lake worth,wellington,plantation.zzzz

Summary
Cancer as a Parasitic Disease
Article Name
Cancer as a Parasitic Disease
Description
Cancer as a Parasitic Disease
Author
jeffrey dach md