Helminth infection–induced malignancy

Infection with some helminth pathogens represents a biological carcinogenInfectious diseases cause more than 20% of cancers in the developing world [1].About a dozen pathogens including Epstein-Barr virus and human T cell lymphocytotropic virus 1 are among the well-known examples.In addition, infection with several trematodes, which are eukaryotes, can cause malignancy.The International Agency for Research on Cancer categorizes infection with the fish-borne trematodes Opisthorchis viverrini and Clonorchis sinensis and the blood fluke Schistosoma haematobium as Group 1 biological carcinogens [2]. In addition to parasitism directly damaging development, health, and prosperity of infected populations, infection with these helminths leads to cholangiocarcinoma (CCA) (bile duct cancer) and squamous cell carcinoma (SCC) of the urinary bladder, respectively [2].By contrast, infection with phylogenetic relatives, also trematodes of the phylum Platyhelminthes and also major pathogens, is not carcinogenic.These irregularities suggest that either helminth-specific metabolites contribute to tumorigenesis and/or that certain tissues or organs are particularly susceptible to infection-induced malignancy.Moreover, each of these helminth infections must be viewed holistically in the context of a perfect storm of risk for cancer (see [3]). Helminth infection-induced cancers O. viverrini and C. sinensis infection-induced cholangiocarcinomaInfection is accomplished by ingestion of undercooked freshwater fish infected with the metacercaria stage of these species of liver flukes.Human infection leads to hepatobiliary disease, including cholangitis and periductal fibrosis.In liver fluke-endemic regions, infection is the major risk factor for CCA [2,4,5].CCAs are slow-growing adenocarcinomas that metastasize to distant sites due to proximity to lymphatic vessels.Liver fluke-related CCA is often diagnosed at an advanced stage, when the primary cancer is no longer amenable to curative surgery [5].The mechanism(s) by which infection initiates genetic lesions that eventually culminate in CCA is not understood, although it is likely to be multifactorial, involving biliary tract and systemic chronic inflammation and associated endogenous nitrosation [6,7], secretion of mitogens and other mediators by the parasite, and cofactors including dietary preferences for nitrosamines-rich foods [4, 8, 9] (Fig 1).