Parasite Infection, Carcinogenesis and Human Malignancy

Abstract

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.

Keywords: Carcinogenesis; Chagas disease; Infection-associated cancer; Malaria; Opisthorchiasis; Schistosomiasis; Strongyloidiasis.

Fig. 1

Proposed mechanisms of carcinogenicity induced by infection with the liver and blood flukes Clonorchis, Opisthorchis and Schistosoma species. The chronic inflammation during Clonorchis, Opisthorchis and Schistosoma infections leads to the activation of signaling pathways including p53, NF-κB, Jak/Stat and Rb that could generate somatic mutations and/or activate oncogenes. Fluke-derived products and metabolites secreted to the host microenvironment may induce metabolic processes including oxidative stress that facilitate damage to the chromosomal DNA of proximal epithelial cells, specially cholangiocytes and urothelial cells for the liver and blood flukes, respectively. In addition, physical damage of host tissues during the development of parasites together with the active wound healing process lead to increased cell transformation and proliferation, which also are associated with the DNA damage. Combined parasite-host interaction events (chronic inflammation, parasite-derived products, and physical damage) and their combined effects on the chromosomes and fates of cells lead to the modification of the cell growth, proliferation and survival that in turn initiate and promote malignancy.

Fig. 2

Proposed mechanisms of induction of Epstein-Barr virus driven Burkitt lymphoma by falciparum malaria. Plasmodium falciparum infected red blood cells (iRBC) bind to the Epstein-Barr virus (EBV) latently infected B cells through the CIDR1α domain of P. falciparum erythrocyte membrane protein 1 (PfEMP1) that lead to the expansion of the latently infected B cell pool and/or lead to the reactivation of EBV. The interaction between iRBCs and EBV-infected B cells in the germinal center (GC) also results in the increased expression of the Activation-Induced cytidine Deaminase (AID). The AID in turn contributes to break host DNA at the immunoglobulin (Ig) or/and highly transcribed regions, to activate oncogenes (c-Myc) and to induce somatic mutations. The AID also induces the chromosomal rearrangement especially the translocation between Ig regions and c-Myc oncogene. All these processes lead to the genomic instability that can drive the proliferation and differentiation of B cells in GC and subsequently lead to the emergence of a malignant B-cell clone. In addition, the binding of iRBC to the dendritic cells (DCs) could lead to a modification of DC functions that contributes to suppress EBV-specific T-cell immunity (CD8⁺ and CD4⁺ T cells), therefore resulting in the loss of controlling the expansion of EBV-infected B cells including emergent Burkitt lymphoma clones.

Fig. 3

Paradoxical roles of Chagas disease, infection with Trypanosoma cruzi, in carcinogenesis. Infection with Trypanosoma cruzi has been proposed in both carcinogenesis and in inhibition of carcinogenesis. T. cruzi has antitumor effects by inducing host immunity against tumor. T. cruzi expresses a calreticulin (T. cruzi calreticulin, TcCRT) that can directly interact with endothelial cells and inhibit their proliferation, migration and capillary morphogenesis as well as inhibit tumor cell growth. The DNA mismatch repair protein (TcMSH2), a central component of the mismatch repair (MMR) machinery in T. cruzi, allows T. cruzi to respond effectively to the oxidative stress during infection. The oxidative stress mediated by alkylating agents and hydrogen peroxide leads to carcinogenesis by damaging DNA. The TcMSH2 protein of T. cruzi may also contribute to protect host chromosomes from oxidative stress during infection, and therefore consequently inhibit tumorigenicity. On the other hand, T. cruzi may also cause cancer by inducing somatic mutation and genomic imbalance during chronic inflammation. However, the molecular details of this latter phenomenon are yet not understood.