However, these studies might suggest that bacteria are not sufficient to induce cancer by their own. Hence, tumor development AZD2281 in vivo might require independent mutations in the oncogenic signaling pathways together with chronic inflammatory conditions which are needed to promote, propagate, and spread tumor lesions [88]. Induction of uncontrolled cellular proliferation In the presence of wall extracted proteins of S. bovis/gallolyticus, Caco-2 cells exhibited enhanced phosphorylation of 3 classes of mitogen activated protein kinases (MAPKs) [38]. Several reports showed that MAPKs activation stimulates cells to undergo DNA synthesis and cellular uncontrolled proliferation [112–114] (Figure

1). Therefore S. bovis/gallolyticus proteins could promote cell proliferation by triggering MAPKs which might increase the incidence of cell transformation and the rate of genetic mutations. Furthermore, MAPKs, particularly p38 MAPK, can induce COX-2 which is an important factor in tumorogenesis [29, 115] up-regulating the expression of NFkB which is considered the central link between inflammation and carcinogenesis, namely, inflammation-induced tumor progression [92]. Colonization of Streptococcus gallolyticus in colorectal mucosa The association of S. bovis/gallolyticus with colorectal cancer has usually been described through the incidence of S. bovis/gallolyticus

bacteremia and/or endocarditis [1–4, 44]. On the other hand, little CHIR-99021 bacteriological research has been done [116, 117] on elucidating the colonization of S. bovis/gallolyticus in tumor lesions of colorectal cancer to confirm or refute, on solid bases, the AZD8931 direct link between colorectal cancer and S. bovis/gallolyticus. Previous studies [116, 117] did not find clear evidence for the colonization of S. bovis/gallolyticus in colorectal tumors. This might be attributed to the complete reliance on bacteriological methods rather

than more sensitive molecular assays for the detection of S. bovis/gallolyticus nucleic acids. A recent study done by our team assessed the colonization of S. bovis/gallolyticus in the colon [40]. In this study, S. bovis/gallolyticus-specific primers and probes were used in PCR and in situ hybridization (ISH) assays, respectively, along with bacteriological isolation of S. bovis/gallolyticus to detect/isolate Gemcitabine manufacturer S. bovis/gallolyticus DNA/cells from feces, tumor mucosal surfaces, and from inside tumor lesions. S. bovis/gallolyticus was remarkably isolated, via bacteriological assays, from tumor tissues of colorectal cancer patients with history of bacteremia, 20.5%, and without history of bacteremia, 12.8%, while only 2% of normal tissues of age- and sex- matched control subjects revealed colonization of S. bovis/gallolyticus. On the other hand, the positive detection of S. bovis/gallolyticus DNA, via PCR and ISH assays, in tumor tissues of colorectal cancer patients with history of bacteremia, 48.7 and 46.