Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity. 1. Introduction Cancers are characterized by uncontrolled growth of abnormal and transformed cells, which can invade adjacent tissues. The global burden of cancer in 2012 was estimated to be 14.1 million new cases and 8.2 million related deaths (WHO, 2015). Six types of cancers including lung, liver, stomach, colorectal, breast, and esophagus cancers are the most common causes of cancer death; four of these (liver, stomach, colorectal, and esophagus cancers) are often associated with distinct infectious diseases (WHO, 2015). Multiple factors can significantly contribute to carcinogenesis (WHO, 2015). Meetings of experts from diverse fields of cancer research held at the International Agency for Research on Cancer (IARC) from 2008 to 2009 have reassessed and classified human carcinogens into “discrete” groups including infectious pathogens (Bouvard et al., 2009, IARC, 2012). Infections with eleven species of pathogens associated with cancers are classified as Group 1 carcinogens, definitely “carcinogenic to humans”, by the IARC. These agents include Helicobacter pylori, hepatitis B virus (HBV), hepatitis C virus (HCV), Opisthorchis viverrini, Clonorchis sinensis, Schistosoma haematobium, human papillomavirus (HPV), Epstein-Barr virus (EBV), human T-cell lymphotropic virus type 1 (HTLV-1), human herpes virus type 8 (HHV-8) and human immunodeficiency virus type 1 (HIV-1) (Bouvard et al., 2009, IARC, 2012, de Martel et al., 2012). Among parasitic diseases, infections with the two fish-borne liver flukes of the family Opisthorchiidae (trematodes), specifically Opisthorchis viverrini and Clonorchis sinensis, can induce cholangiocarcinoma, and infection with the blood fluke Schistosoma haematobium may cause cancer of the urinary bladder (Bouvard et al., 2009). Although malaria per se is not considered carcinogenic to humans by the IARC, the geographical association between the occurrence of malaria and that of Burkitt lymphoma provides a clue that malaria plays as a co-carcinogenic factor, together with EBV infection, for the development of Burkitt lymphoma (Molyneux et al., 2012). Other species of the genera Opisthorchis and Schistosoma are thought likely to be carcinogenic (Sripa et al., 2007, Pakharukova and Mordvinov, 2016). Intriguingly, Trypanosoma cruzi, the etiological agents of Chagas disease, displays apparently paradoxical roles in malignancy in exerting carcinogenic and anticancer properties (Krementsov, 2009, Sacerdote de et al., 1980). Potential causative roles of other parasitic infections have been postulated (Machicado and Marcos, 2016). Here, we summarize current concepts and facts on associations of parasite infections, namely schistosomiasis, opisthorchiasis, clonorchiasis, strongyloidiasis, malaria, and Chagas disease with human cancers and review mechanisms by which parasites may promote, or impede carcinogenesis (Table 1). Table 1 Parasitic pathogens and infection-associated malignancy. Parasitic pathogens Disease Endemic areas Associated cancer Proposed mechanism of carcinogenesis Blood flukes Schistosoma haematobium Schistosomiasis sub-Saharan Africa Urinary bladder cancer, adenocarcinoma, squamous cell carcinoma Inflammation, oxidative stress caused by parasite-derived molecules Schistosoma japonicum Schistosomiasis sub-Saharan Africa Colorectal cancer, rectal cancer, squamous cell carcinoma, membranous nephropathy, metastatic lung cancer Inflammation, oxidative stress caused by parasite-derived molecules Schistosoma mansoni Schistosomiasis sub-Saharan Africa Adenocarcinoma, colorectal cancer, hepatocellular carcinoma Inflammation, oxidative stress caused by parasite-derived molecules Liver flukes Opisthorchis viverrini Opisthorchiasis Southeast Asia Cholangiocarcinoma Inflammation, oxidative stress caused by parasite-derived molecules, cell proliferation, H. pylori mediated induction Clonorchis sinensis Clonorchiasis China, Korea, northern Vietnam Cholangiocarcinoma Inflammation, oxidative stress caused by parasite-derived molecules, cell proliferation Opisthorchis felineus Opisthorchiasis Europe and Russia Cholangiocarcinoma Inflammation, oxidative stress caused by parasite-derived molecules, cell proliferation Plasmodia species Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium knowlesi Malaria sub-Saharan Africa, Southeast Asia Burkitt lymphoma (indirect carcinogenicity) Expansion of the EBV-infected B cell population, Suppression of EBV-specific T-cell immunity, Reactivation of EBV, AID-dependent genomic translocation Strongyloides stercoralis Strongyloidiasis sub-Saharan Africa, South and Central America Southeast Asia HTLV-1 induced lymphomas/leukemias (indirect carcinogenicity) Colon adenocarcinoma Stimulate HTLV-1 replication, Oligoclonal expansion of HTLV-1-infected lymphocytes Trypanosoma cruzi Chagas’ disease South and Central America Gastrointestinal cancer, Uterine leiomyoma Unknown Open in a separate window Go to: 2. Schistosomiasis and Cancer Schistosomiasis is a neglected disease caused by infection with blood fluke trematodes of the genus Schistosoma. Out of 207 million cases of schistosomiasis currently estimated worldwide, 90% occur in sub-Saharan Africa (Steinmann et al., 2006). Schistosomiasis is considered the most important helminth parasite of humans in terms of morbidity and mortality. The five species of Schistosoma that infect humans are Schistosoma haematobium, S. mansoni, S. japonicum, S. intercalatum, and S. mekongi. Most human infections are due to S. haematobium, S. mansoni, and S. japonicum. Of those, S. haematobium is the most ubiquitous species in Egypt and in sub-Saharan Africa and causes urogenital schistosomiasis (UGS). The prevalence of schistosomiasis is associated with exposure-related factors, in particular with a favourable environment for the imperative intermediate host snails, sub-optimal sanitation infrastructure, and host genetic factors. Adult worms are usually found in human hosts; their interactions with the host and parasite-derived products including their eggs strongly induce carcinogenesis (Brindley et al., 2015). With regard to schistosomiasis at large, clearly UGS i.e. chronic infection with S. haematobium, is carcinogenic and thus classified as a Group 1 carcinogen by the IARC (IARC, 2012). Any carcinogenicity of infection with other schistosomes is far less evident. Liver and colorectal cancers and lymphoid tumors may be associated with chronic schistosomiasis. Nonetheless, infection with S. japonicum is classified by the IARC as Group 2B, i.e. possibly carcinogenic to …
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