The Possible Involvement of Protozoans in Causing Cancer in Human

protozoans have also been found to cause cancer in humans and animals. They are eukaryotic, unicellular, anthropozoonotic microorganisms causing several life-threatening diseases and cancer in humans. While a plethora of good pieces of information was gathered while documenting the role of several protozoans causing cancer in humans, only Plasmodium falciparum has been categorized by the IARC as Group 2A carcinogen. However, certain other protozoan parasites have also got their ability to cause cancer in humans via the integration of protozoan DNA sequences in the host cells. Protozoans cause the stimulation of cell division and proliferation of the host cells by the release of reactive oxygen and nitrogen radicals, DNA damage and the p53 gene inhibition. The present review discusses some cancer-causing protozoan parasites like Leishmania donovani, Trypanosoma brucie, Toxoplasma gondii, Trichomonas vaginalis, Blastocystis hominis, Theileria microti and Cryptosporidium parvum including Plasmodium falciparum in the light of recent researches done so far in the field of microbial origin of cancer.


INTRODUCTION
Ascertain parasitic infections cause cancer in humans and animals, they have been considered a big problem for us. Similarly, these problems are more exaggerated when an infection even after treatment becomes cancerous in the future. Protozoans are one of them. They are unicellular, eukaryotic and zoonotic microorganisms mostly found in animals and humans. These protozoans in association with a variety of life-threatening diseases also developed cancer in humans. Plasmodium falciparum has been playing as a cofactor in association with the Epstein Barr virus enhancing the development of Burkitt lymphoma in humans (Flora and Maestra 2015). Leishmania donovani causes skin cancer, leukaemia and Hodgkin lymphoma (Sah et al. 2002, Mangoud et al. 2005, Domingues et al. 2009, Al-Kamel 2017. While there are reports that Trypanosoma cruzi developed gastrointestinal, colon and uterine cancer (Sacerdote et al. 1980, Addad et al. 2002, Murta et al. 2002, Toxoplasama gondii, a causative agent of toxoplasmosis causes brain and breast cancer in human (Marion et al. 2012, Narges et al. 2017.
Similarly, Trichomonas vaginalis is linked with cervical cancer (Sayed-El-Ahl 2002), Blastocystis developed colorectal cancer (Steer 2007, Amr et al. 2017 12,13 , Theileria induces leucocyte transformation (Medjkane et al. 2014) and Cryptosporidium causes digestive cancer in human and animals (Certaid et al. 2010, Gabriela et al. 2012. The present paper deals with the study of various protozoans involved in the development of cancer in humans.
DISCUSSION Recent advances in the field of infectious diseases have led to significant revelations to clarify the relationship between infective protozoans and cancer in humans. The present review discusses some of the cancer-causing protozoans with their possible mechanisms involved. Protozoan parasites have got their oncogenic ability to cause cancer in humans. Insertion of oncogenic DNA sequences in the host genome, inhibition of tumor suppressor gene and the stimulation of cell division cause cancer. Moreover, chronic inflammations at the site of infection having DNA damage, the release of reactive oxygen and nitrogen radicals and developing cell proliferation promoted neoplasia in the host. However, since the removal of infective agents may result in the removal of tumor development from the host, the same notion might be used as one of the thrust areas for research in the future in the same field. (Heussler et al. 2001, Khurana et al. 2005, Reuter et al. 2010, Van et al. 2017.
In this review, we have discussed certain protozoan parasites causing not only life-threatening diseases but also developing cancer in humans. They are Plasmodium falciparum, Leishmania donovani, Trypanosoma brucie, Toxoplasma gondii, Trichomonas vaginalis, Blastocystis hominis, Theileria microti and Cryptosporidium parvum. They are being discussed serially as under:

Plasmodium falciparum (Malaria):
Plasmodium falciparum is the most lethal form of malarial parasite found in humans. This is a single-cell protozoan parasite being transmitted through the bites of female anopheles mosquitoes. The common symptoms of malaria are tiredness, fever, headache, vomiting and feeling cold. In severe cases, it may cause yellowing of skin, seizures, coma and death. The disease is usually being treated with some antimalarial drugs like quinine and artemisinin. There is still no vaccine available for the control of malaria (Carter and Mendis 2002, Su and Miller 2015, Kai 2017.
Plasmodium falciparum has been found as a co-factor for the development of cancer in humans. The hypothesis that Plasmodium falciparum plays a key role in the production of endemic Burkitt's lymphoma (eBL) has been supported by several studies done so far in the field of parasitic infections (Thorley et al. 2016). Several epidemiological studies supported the view as eBL is more frequently found in the areas where malaria is endemic. Malarial antibodies and the Epstein Barr virus (EBV) showed a strong and significant association in the development of eBL. However, more work is needed to complete the mechanism (Chene et al. 2007, Orem et al. 2007, Carpenter et al. 2008and Bornkamm 2009. P. falciparum has been associated with the development of blood cancer, Burkitt's lymphoma and is classified as a Group 2A carcinogen, which is probably carcinogenic in humans (Flora and Maestra 2015). Burkitt's lymphoma was discovered in African children by Denis Burkitt in 1958. It was found subsequently that this cancer is caused by a virus named Epstein Barr virus. And, EBV is classified as a Group 1 carcinogen by the IARC (Bouvard et al. 2009). Later on, it was also realized that EBV in association with P. falciparum enhances the incidence of Burkitt's lymphoma. Also, the cases of Burkitt's lymphoma decreased in places where malaria was found in control (Geser et al. 1989). In Burkitt's lymphoma, the transformations causing lymphoma took place using EBV viral proteins such as EBN-1, EBNA-2, LMP-1 and LMP2A (Rajcani et al. 2014). P. falciparum by infecting erythrocytes directly binds to lymphocytes secreting IgM and cytokines causing DNA damage, mutation, proliferation and differentiation in lymphocytes. Finally, the damaged DNA by replicating indefinitely causes cancer (Thorley et al. 2016, Van et al. 2017, Yasunaga and Matsuoka 2018. Leishmania (Black fever or Kala-Azar): Leishmaniasis is a chronic widely prevalent, intracellular, anthropozoonotic protozoan infection in mammals including humans of tropical and subtropical regions of the world. This is classified as a neglected tropical disease (NTD) because it remains untouched and under-reported by researchers causing significant morbidity and mortality in humans. Leishmania is graded as the second largest leading cause of death after malaria worldwide (Mc Guire 2015). There are three types of leishmaniasis caused by the various species of Leishmania visceral, cutaneous and mucocutaneous leishmaniasis. Visceral leishmaniasis (VL) is also called Kala-Azar or black fever which affects the internal organs, usually the spleen, liver and bone marrow. It gives the diagnostic darkening of the skin as black (Osakwe et al. 2013, Chisti et al. 2016, Al kamel 2018.
Leishmania is graded as the second largest leading cause of death after malaria worldwide (Mc Guire 2015). Although this is a neglected tropical disease, a growing number of studies speculate on a possible causal relationship between leishmaniasis and the development of cancer in humans and animals (Al-Kamel 2017). Several scientists believe that it could be a result of either misdiagnosis or mimicking the symptoms that appeared. Sometimes, to cure the disease, when we practice various unsafe measures indiscriminately developed cancer in humans. (Kopterides et al. 2007, Khorsandi et al. 2009, Evers et al. 2014, Celentano et al. 2015, Cobo et al. 2016, Gul et al. 2016, Oetken et al. 2017, Van et al. 2017, Aurelie and Gregoy 2019). However, further research is required to establish the fact. There are some other reports also found in literature establishing the truth that in association with leishmaniasis, it causes malignancy in humans and animals. Some of them are basal cell carcinoma, leukaemia, ocular epidermoid carcinoma and Hodgkin lymphoma (Matayoshi et al. 2000, Sah et al. 2002, de Vasconcelos et al. 2014Chisti et al. 2016.
Chronic irritations, genome instability, mutations in the host cell genome and cell proliferations have contributed to causing cancer in the host cells affected by leishmania. Similarly, the inflammations caused by the infection, inhibition of apoptosis and the inhibition of tumor suppressor gene could lead to progression in malignancy. In leishmaniasis, oxidative stress increases the DNA damage in the lesions. Nitrative DNA damage causes proliferative changes in the epidermal cells of cutaneous leishmaniasis (Coussens 2002, Kocyigit et al. 2005, Mangoud et al. 2005, Sawa and Ohshima 2006.
In India, the main parasite causing the disease is Leishmania donovani (Bhunia et al. 2013). The clinical diagnosis is made with the help of serological tests such as DAT and rk39 dipstick tests. The rapid immunochromatographic test (ICT) consisting of rK39 is widely used for the detection of visceral leishmaniasis with the help of serum provided. Liposomal amphotericin B is the first choice of drug by physicians to treat visceral leishmaniasis. Miltefosine is the first oral drug treatment for this disease. However, this is teratogenic and could never be prescribed for a pregnant woman. Recently, the Indian government has approved the broad-spectrum antibiotic paromomycin for use and sale in August 2006. Currently, there is no vaccine available for the prevention of the disease. The most effective method for disease control is the prevention of bites by sandflies (Lockwood and Sundar 2006, Sundar et al. 2010, Rijal et al. 2013, Gillespie et al. 2016.

Trypanosoma brucei (Trypanosomiasis):
Trypanosomiasis is a kind of disease that causes sleeping sickness in humans and nagana in cattle in 36 countries of sub-Saharan Africa. This is caused by a blood parasitic protozoan Trypanosoma. There are two main types of trypanosomiasis distributed geographically such as African and American trypanosomiasis. American trypanosomiasis is also known as Chagas's disease. The disease is named after Carlos Ribeiro Justiniano Chagas, a Brazilian physician and researcher who discovered the disease in 1909. While African trypanosomiasis is transmitted by the urine and faeces of the tsetse fly (Glossina), the American trypanosomiasis is transmitted by a triatomine kissing bug (Wiser 2011, Coura 2013).
Further, African and American types of trypanosomiasis are caused by T. brucei and T. cruzi respectively (Fevre et al. 2008). The first stage is the hemolymphoid stage in which the trypanosomes multiply in subcutaneous tissues, blood and lymph. This is characterized by fever, headache, joint pain, itching and swollen lymph nodes (Matthews 2005). The second stage is known as the neurological or meningoencephalitis stage. In this stage, the pathogen crosses the bloodbrain barrier to infect the CNS and is characterized by disturbances in mood and behavior, sense and coordination and sickness in sleep (Lutje et al. 2010, Radwanska 2010. The other clinicopathological symptoms are heart anomaly (Hagar and Rahimtoola 1995) and dilatation of the colon (Kobayashi et al. 1992). Chagasic megaesophagus, achalasia of the pylorus and cholelithiasis (Pinotti et al. 1991).
Trypanosoma cruzi, the causing agent of the Chagas disease has a dual role in the development of cancer including both carcinogenic and anticarcinogenic properties (Kallinikova et al. 2001, Zhao et al. 2015. There are reports that T. cruzi developed esophageal carcinogenesis leiomyosarcoma (Addad et al. 1999, Bellini et al. 2010), gastrointestinal cancer (Sacerdote et al. 1980), colon cancer (Addad et al. 2002 and uterine leiomyoma (Murta et al. 2002). A kind of report also evidenced that T. evanshi also causes leukemia and hepatocarcinoma in humans (Safaa 2019).
The diagnosis of Trypanosoma is based on the detection of the pathogen in body fluids. It should be done as early as possible to avoid the progression of the disease further.
The disease is cured if diagnosed and medicated early but surely proved fatal if left untreated. While the treatment is easier in the first stage of the disease, the second stage of treatment depends upon the choice of drugs that crosses the blood-brain barrier. Further, the drugs used in the treatment of the first stage are pentamidine, melarsoprol, eflornithine, nifurtimox, fexinidazole. Similarly, the drug used to treat both stages is fexinidazole (Barrett 2010). Lastly, since all the drugs available today have always been toxic having severe side effects, a new drug is urgently required to treat the disease safely. Similarly, as no effective vaccine currently exists today for the same purposes, a new vaccine is the subject of current research (Magez et al. 2010).

Toxoplasma gondii (Toxoplasmosis):
Toxoplasma gondii is a most neglected obligate protozoan parasite inhabiting most warm-blooded animals like monkeys (Huessler et al. 1971 Woodhall et al. 2014). However, the only known definitive host for T. gondii is the domestic cat and its relatives. While the cats become infected by the ingestion of sporulated oocysts, the humans are infected mainly by eating undercooked meat, consumption of contaminated foods, fruits, vegetables and water with cat faeces, vertical transmission by the placenta from mother to fetus and by cleaning the boxes of pet cats (Malik et al. 2017, Marques et al. 2020. Initially, an individual shows some flu-like symptoms with swollen lymph nodes which disappear after some time but the pathogen remains in the body for a longer period in an inactivated form. It is often reactivated in individuals who are either immunocompromised or immunosuppressed in the future (Montaya and Remington 2008). Toxoplasmosis can be very harmful to pregnant women and their developing babies. As the infection usually spreads via cat faeces, a pregnant woman should never come in contact with the same infection (Dubey and Carpenter 1993). It could have some fatal consequences for her babies causing serious eye defects and brain damage at birth (Jones et al. 2001). The infants infected before birth often show no symptoms at birth but the symptoms appear gradually after birth with the loss of vision, physical and mental disability and seizures (Naqid et al. 2019).
In humans, the infective agents of toxoplasmosis as tissue cysts are most commonly found in the brain, myocardium, eyes, skeletal muscle and breasts causing cancer of the respective organs (Zhang et al. 2002, Khurana et al. 2005, Marion et al. 2012, Zhao et al. 2015, Narges et al. 2017. The potentiality of pituitary adenoma has been suspected with the infection of Toxoplasma gondii (Zhang et al. 2002). This is found as the tumor promoter as has been reported in ocular tumors, meningioma, leukaemia and lymphoma (Khurana et al. 2005). Currently, brain and breast cancers are more commonly tagged with the infection of Toxoplasma gondii in humans (Marion et al. 2012, Narges et al. 2017. The clinicopathological diagnosis of T. gondii is done either by the staining of tissue cysts (Kaliakin 1972) or serology (Simon et al. 2020). T. gondii DNA is also detected via the polymerase chain reaction. Congenital infections are achieved by the detection of T. gondii DNA in the amniotic fluid using PCR. (Geng et al. 2001, Naqid et al. 2019, Alessia et al. 2020, Marques et al. 2020. Most healthy people usually recover without any treatment but for an immunocompromised patient, the disease is often proved to be fatal if not treated well within time. In general, the patients are being treated with the drug combination of pyrimethamine, sulfadiazine with folinic acid (Maldonado and Read 2017). A drug named aureobasidin is also being tried (Sabrina et al. 2005).

Trichomonas vaginalis (Trichomoniasis):
Trichomonas vaginalis is the causative agent of trichomoniasis. This is an anaerobic, flagellated, parasitic protozoan. T. vaginalis is the most widely studied parasite of all the trichomonads. As humans are the only natural reservoir of T.vaginalis this is usually transmitted either sexually or by close contact with others (Dino et al. 1998). This is generally found in association with other infections like peneumocystosis, candidiasis and HPV infections (Boyle et al. 1989, Duboucher et al. 2003& 2007. The clinicopathological symptoms of the disease are characterized by itching, redness, irritation and an unusual discharge from the vagina. Moreover, with the same infection rates in both genders, this is usually asympotomatic in men. As this is a sexually transmitted disease, the pathogen usually resided in the lower urinogenital tract of the human female. It has been reported to cause pelvic inflammatory disease and cervical cancer. Cervical cancer is a malignant neoplasm characterized by abnormal vaginal bleeding but, sometimes this is quite asymptomatic until cancer has progressed to an advanced stage (Boyle et al. 1989, Yap et al. 1995, Dino et al. 1998, Sayed-el-Ahl et al. 2002. Further, T. vaginalis principally infects the squamous epithelial cells of the genital tract. This is chiefly a disease of reproductive years and rarely seen in an individual before menarchy or after menopause. It causes adnexitis, pyosalpinx, endometritis, cervical erosion and infertility. The patients also suffer from premature labour, premature birth, or birth with lowweight infants. In addition, it causes prostate cancer in humans. However, the reports regarding the pathogen to causes cancer are still contradictory. Larger studies are required to explore the possible effect modifications further (Stark et al. 2009, Sutcliffe et al. 2009).
Trichomonas vaginalis is diagnosed by papnicolaou staining technique with the help of acridine orange (Fripp et al. 1975), periodic-acid-Schiff (Rodriguez et al. 1973 and Leishman (Levett 1980) reagents for direct microscopy (Spence et al. 1980). The antgen-antibody test, and recombinant DNA technology with PCR have also been used up in clinical laboratories to improve the efficacy of T. vaginalis diagnosis (Levett 1980). Metronidazole marketed under the trade name "flagel" is the first choice of drug for physicians to remove the infection of trichomoniasis (Hayward and Roy 1976). Other nitroimidazoles such as tinidiazole, secnidazole, nimorazole, carnidazole, ornidazole and flunidazole have also been tried worldwide for the treatment. (Pereyra et al. 1972, Hayward and Roy 1976, Sucharit et al. 1979, Chaudhary and Drogendijk 1980, Fugere et al. 1983. Similarly, the vaginal preparation of clotrimazole is also found effective for the removal of T. vaginalis infection (Lossick et al. 1986, Lossick andKent 1991).

Blastocystis hominis (Blastocystosis):
Blastocystis is one of the most neglected common protozoan parasites living in the gastrointestinal tract causing a disease known as Blastocystosis in humans and animals. Various types of Blastocystis exist infecting farm animals, birds, reptiles, amphibians, rodents, fishes and even cockroaches. This is a kind of zoonotic disease usually transmitted via the faecal-oral route (Yoshikawa et al. 2004, Parkar et al. 2007, Stensvold et al. 2009 et al. 2015). This is also linked with irritable bowel syndrome and arthritis (Lee et al. 1990, Roshtami et al. 2017. Blastocystis has been shown to produce inflammatory cytokines interleukin-8 having an important role in rheumatoid arthritis. It causes colorectal cancer and acquired immunodeficiency syndrome in humans. Blastocystis hominis modulates immune responses and cytokine release in colonic epithelial cells. Blastocystis also secreted an enzyme protease that eventually led to the self-destruction of intestinal cells causing enhanced apoptosis. It can proliferate human colorectal cells via abnormal apoptosis and protein disintegration. Similar studies have also shown that Blastocystis elevated the oxidative stress to form reactive oxygen causing the cells more toxic and cancerous in an easier way (Koltas et al. 1999, Long et al. 2001, Puthia et al. 2006, Amr et al. 2017.

Theileria microti (Theileriosis):
Bovine theileriosis is a cattle disease found in tropical and subtropical countries caused by several species of Theileria belonging to the phylum Apicomplexa (Grech et al. 2016). Theileria microti is a blood-borne microorganism transmitted by deer ticks. This is responsible for the zoonotic disease named human theileriosis similar to babesiosis, a malaria-like disease causing fever, lymphadenopathy and hemolysis. It was previously described as Babesis microti (Uilenberg 2006, Vannier and Krause 2012, Onyinyechukwu et al. 2020. This is an intracellular parasite particularly pathogenic in cattle causing the lymphoproliferative disease which is often lethal similar to some human leukaemias. It causes leukocyte transformations via antiapoptosis residing freely in the host leukocyte modifying the host cell cytoskeleton (Heussler et al. 2002, Dobbelaere and Rottenberg 2003, Lizundia et al. 2006, Branco et al. 2010. Theileria induces oxidative stress via elevated reactive oxygen species (ROS) and hypoxia-inducible factor 1 α (HIF 1 α) activation causing host leukocytes transformation (Dobbelaere 2003, Medjkane et al. 2014. HIF 1 α activation leads to an increased production of lactic acid from glucose mediated by the seventh hallmark of cancer known as the Warburg effect (Denko 2008, Yeung et al. 2008, Koppenol et al. 2011. The increased glycolysis involving elevated glucose uptake in cancer cells has already been considered to be an important feature during malignant transformations (Shaw 2006). However, these cancer characteristics are reversible when treated with the host cells with a theilericidal drug named buparvaquone. It stops the proliferation maintaining the normal apoptosis (Chaussepied and Langsley 1996, Muraguri et al. 1999, Medjkane et al. 2014. Live, attenuated and DNA vaccines are now available to control theileriosis (Hemmink et al. 2016, Nene andMorrison 2016).
The diagnosis of theileriosis is obtained by blood or lymph node smears with the help of Giemsa-stain to detect piroplasm in erythrocytes or macro-schizonts in leukocytes. In addition, serological and molecular techniques like ELISA and PCR have also been employed (Shayan and Rahbari 2005, Khatoon et al. 2013, Rajendran and Ray 2014. Similarly, a microarray kit is designed for the detection of various species of Theileria (Abanda et al. 2019).

Cryptosporidium parvum (Cryptosporidiosis):
Cryptosporidium parvum is an intracellular protozoan parasite ubiquitous in nature. This is a water-borne protozoan isolated from the stool of a patient who was drowned in a river. The strain was inoculated in a mouse causing infection. It induces invasive gastrointestinal and biliary adenocarcinoma (Gabriela et al. 2012, Osman et al. 2017. Cryptosporidiosis is found in almost all vertebrates including amphibians, reptiles, birds, humans and other mammals. The invasive oocyst stage is more resistant to temperature and saltwater. The infection is easily transmitted via contaminated water and unhygienic condition through the fecal-oral route. This is worldwide in distribution creating food and waterborne health problems as a frequent cause of watery mucous diarrhoea in humans and animals. This is mostly affecting children under the age of five years. However, a competent patient may usually recover within two weeks (Mac et al. 1994, Putignany and Menichella 2010, Benamrouz et al. 2012.
The immunocompromised patients are more easily affected by the Cryptosporidium. This is an opportunistic infection with life-threatening diarrhoea, especially those undergone antiretroviral therapy. It may cause stomach cramps, stomach pains, nausea, vomiting, diarrhoea, dehydration, weight loss and fever (Hunter andNichols 2002, Remirez et al. 2004). The possible role of cryptosporidiosis in the production of intramucosal adenocarcinoma and cholangiocarcinoma is considered an early sign of invasive cancer and a putative precursor to digestive carcinoma (Izquierdo et al. 1998and Certaid et al. 2010, Gabriela et al. 2012. C. parvum resides on gastrointestinal epithelial cells (Plattner and soldati-favre 2008) developing neoplasia including blunting of the intestinal villi, crypt hyperplasia and inflammation (Sulzyc et al. 2007, Certaid et al. 2010, Benamrouz et al. 2012. Cryptosporidiosis is well documented in AIDS patients causing colorectal cancer in them (Shebl et al. 2012). Several epidemics have been recorded with cryptosporidiosis in the past. In Poland, an epidemiological study shows that 18% of cryptosporidiosis patients were also suffering from colorectal cancer with inhibited apoptosis and disturbed cytoskeleton system in the host cells. Finally, more research is required to establish cryptosporidiosis as a cause of cancer (Heussler et al. 2001, Buda and Pignatelli 2004, Carmen and Cinai 2007, Sulzyc et al. 2007, Striepen 2013, Violetta et al. 2018, Zhang et al. 2020.

CONCLUSION
As the bacterial and viral origin of cancers has already been established, the present review described the protozoans causing cancer in humans. Plasmodium falciparum is associated with the development of Burkitt's lymphoma. This is classified as a Group 2A carcinogen by the IARC (Flora and Maestra 2015). One of the most neglected tropical diseases is leishmaniasis causing black fever in humans. This is graded as the second largest leading cause of death after malaria worldwide. Similarly, a growing number of studies speculate on a possible causal relationship between leishmaniasis and the development of cancer. Another protozoan Trypanosoma crosses the blood-brain barrier in humans to cause sleeping sickness with various neurological CNS disorders. It also causes gastrointestinal, oesophageal, colon, uterine and hepatocarcinoma in humans. Further, the Toxoplasma gondii is a most neglected protozoan parasite inhabiting most warmblooded animals including humans that causes the disease toxoplasmosis. However, the only definitive host for T. gondii is a domestic cat. It can be very harmful to pregnant women and their developing babies. The infective cysts are most commonly found in the brain, myocardium, eyes, skeletal muscle and breasts causing cancer of the respective organs. The next protozoan causing cancer in humans is Trichomonas vaginalis. As humans are the only reservoir of T. vaginalis, this is usually transmitted sexually. It causes cervical cancer in the human female. Similarly, theileriosis is a blood-borne zoonotic disease caused by Theileria microti, an intracellular protozoan parasite causing lymphoproliferative disease and leukocyte transformation. In addition, Blastocystis hominis is a zoonotic protozoan parasite living in the gastrointestinal tracts of different animals and humans. This is usually transmitted by the faecal-oral route. It causes irritable bowel syndrome and arthritis in humans. It has also been linked with colorectal cancer and immunodeficiency syndrome. Lastly, the cryptosporidium parvum is also an intracellular protozoan parasite that induces invasive gastrointestinal and biliary adenocarcinoma and colorectal cancer.