Cryptosporidium parvum-induced ileo-caecal adenocarcinoma and WNT signaling in a rodent model

Abstract

Cryptosporidium species are apicomplexan protozoans that are found worldwide. These parasites constitute a large risk to human and animal health. They cause self-limited diarrhea in immunocompetent hosts and a life-threatening disease in immunocompromised hosts. Interestingly, Cryptosporidium parvum has been related to digestive carcinogenesis in humans. Consistent with a potential tumorigenic role of this parasite, in an original reproducible animal model of chronic cryptosporidiosis based on dexamethasone-treated or untreated adult SCID mice, we formerly reported that C. parvum (strains of animal and human origin) is able to induce digestive adenocarcinoma even in infections induced with very low inoculum. The aim of this study was to further characterize this animal model and to explore metabolic pathways potentially involved in the development of C. parvum-induced ileo-caecal oncogenesis. We searched for alterations in genes or proteins commonly involved in cell cycle, differentiation or cell migration, such as β-catenin, Apc, E-cadherin, Kras and p53. After infection of animals with C. parvum we demonstrated immunohistochemical abnormal localization of Wnt signaling pathway components and p53. Mutations in the selected loci of studied genes were not found after high-throughput sequencing. Furthermore, alterations in the ultrastructure of adherens junctions of the ileo-caecal neoplastic epithelia of C. parvum-infected mice were recorded using transmission electron microscopy. In conclusion, we found for the first time that the Wnt signaling pathway, and particularly the cytoskeleton network, seems to be pivotal for the development of the C. parvum-induced neoplastic process and cell migration of transformed cells. Furthermore, this model is a valuable tool in understanding the host-pathogen interactions associated with the intricate infection process of this parasite, which is able to modulate host cytoskeleton activities and several host-cell biological processes and remains a significant cause of infection worldwide.

Intestinal parasites in cancer patients in the South of Brazil

“…In addition, studies have linked Cryptosporidium spp., among other parasites, to the development of cancer, inasmuch as it is believed that chronic inflammation of the intestinal tract due to the presence of the parasite could induce pathological disorders with adenocarcinoma genesis. Studies have also shown that even low doses of this protozoan may induce gastrointestinal neoplasia (Benamrouz et al, 2014;Oliveira, 2014). Nevertheless, this relationship has not been diagnosed in this study.…”

Carcinogenesis associated with parasites other than Schistosoma, Opisthorchis and Clonorchis: A systematic review

“…The mechanisms of action to promote malignancy from a parasitic infection reported here include chronic inflammation, genomic instability, activation of invasion, angiogenesis and metastasis, dysregulation of tumor suppressor genes, alteration of Wnt pathway, sustained cell proliferation, inhibition of apoptosis, modulation of energetic metabolism and evasion of immune response . Based on our results, it seems that carcinogenesis associated with parasite infections can be triggered by various mechanisms different from that the so‐called “chronic inflammatory infection process” (Table ).…”

“…While local invasion represents the ability to migrate and form distant metastasis, angiogenesis enables to generate neovasculature. Such mechanisms have been described in infection by C. parvum, T. vaginalis, E. granulosus, and Theileria . An animal model demonstrated that having both E. granulosus cystic infection and breast tumors increases the likelihood for the cancer to metastasize into the liver, which is associated with immune evasion of parasite as explained below .…”

“…An animal model demonstrated that having both E. granulosus cystic infection and breast tumors increases the likelihood for the cancer to metastasize into the liver, which is associated with immune evasion of parasite as explained below . Additionally, Theileria has been seen to induce epigenetic changes in the host cell, which has been related to metastasis and angiogenesis . T. vaginalis was found to secrete a macrophage migration inhibitory factor that mimics human homologue to bind the human CD74 receptor, which in turn, leads to increased cellular proliferation, inflammation and invasiveness …”

“…Modulation of the expression or activity of tumor suppressors have been associated with infection by P. fastosum, T. parva and C. parvum. 13,26,27 Enhanced expression of the mouse doubl e minute 2 (mdm2) gene in T. parva-infected cells alters p53 stabilization, which favours cell transformation. 27…”