BOD - Revision - Lent - Edwards - Cancer Lecture 42 - The Causes of Cancer - Viruses? 1 None cause cancer outright: · Chronic infection > cell death + turnover + inflammation · Chronic inflammation > Inflammatory cells such as macrophages and neutrophils are important sources of endogenous oxygen radicals > formation of carcinogenic N- nitrosamines · Inflammatory cells induce genotoxic effects, such as mutations sister chromatid exchanges, and DNA strand breaks · Inflammatory cells also participate in the activation of procarcinogens, such as aromatic amines and polycyclic aromatic hydrocarbons, to their ultimate carcinogenic metabolites (i.e., the final reactive form of the carcinogen) · Some have oncogenic genes/proteins e.g. Helicobacter pylori * Inactivate p53, Rb * HPVs: E6, 7 proteins * Viruses may alter host genome by integrating · Bacteria and parasites: larger have adapted to survive outside cell 1 Bacteria and parasites: · Schistosomes haemotomium> bladder cancer > not every strain * Heavy egg deposits in bladder mucosa and submucosa (also liver) > act as mechanical irritant to the urothelium > inducing chronic inflammatory lesions " Oestrogen derivative protein: metabolised to carcinogen/antigen protein > directly bind to host cell DNA > increase genetic instability chronic tissue injury = promoting factor > increase rate of cell turnover via the induction of restorative hyperplasia and squamous metaplasia At this stage, proliferating cells are not neoplastic but are transitional and non- invasive; most reversible * Some hyperplasia and dysplasia may become irreversible > concomitant exposure to low (sub-carcinogenic) doses of carcinogens e.g., N-nitroso compounds > smoking · Helicobacter pylori > gastric adenocarcinoma + MALT lymphoma (lymphoma associated with intestinal mucosa) Spiral, gram-negative * Colonises mucin layer gastric mucosal cells in antrum Chronic infection > cell death + turnover + inflammation Major inflammation + ulceration: induced IL-8 attracts PMN " Chronic inflammation > exposes proliferating muscosal stem cells to dietary carcinogens + generates mutagenic reactive oxygen " Inflammatory cells such as macrophages and neutrophils are important sources of endogenous oxygen radicals > formation of carcinogenic N- nitrosamines " Inflammatory cells induce genotoxic effects, such as mutations sister chromatid exchanges, and DNA strand breaks
" Inflammatory cells also participate in the activation of procarcinogens, such as aromatic amines and polycyclic aromatic hydrocarbons, to their ultimate carcinogenic metabolites (i.e., the final reactive form of the carcinogen) Destruction epithelial cells by pore-forming vacuolating cytotoxin (VacA) * CagA > obtained from pathogenic strains > in epithelial cells > interferes in signalling pathways > increased cell proliferation > · Viral mechanisms: Rare: cancer kills the host * Broad range of genomes size: Herpes 200kb > HPV 8kb " Compare different ways of cancer induction > number of proteins # Viruses drive a cell to proliferate > induce Direct oncogenic = insertion of additional viral oncogenic genes into the host cell or to enhance already existing oncogenic genes (proto-oncogenes) in the genome " must have at least one virus copy in every tumour cell expressing at least one protein or RNA " foreign virus antigens are expressed in