Previously we discussed groups of viruses that introduce oncogenes into the host as part of their pathogenicity (1). Dysregulated host cell growth may be advantageous to endogenous retroviruses, as forcing infected cells to divide can mediate passive replication of the viral genome. In this sense, viral oncogenes provide an evolutionary benefit to these pathogens. However, viruses are not the only pathogens associated with cancer; certain species of bacteria, most notably the gastric parasite Helicobacter pylori, can also contribute to cancer formation (2)(3). Whether or not bacteria do utilize oncogenes to induce transformation is still a new and undeveloped field of research.
Unlike viruses, bacteria are generally free-living organisms and are not currently known to integrate their genomic information into human host cells. They are therefore unlikely to insert oncogenes directly into the host or make use of gene insertion to disrupt gene regulation. Bacteria do, however, have the ability to deliver pathogenic gene products directly into a host via elegant secretion systems (4). Recently, it has been shown that certain strains of H. pylori insert the CagA oncoprotein into host gastric cells using a Type IV secretion system, providing novel evidence of an oncoprotein of bacterial origin (5).
Helicobacter pylori and the CagA Oncoprotein
Infection with the gram-negative bacterium Helicobacter pylori has an established causative link to gastric cancers, resulting in the World Health Organization declaring it a Class I Carcinogen in 1994 (6). It was first noted that only H. pylori strains that produce functional CagA protein could activate AP-1 signaling and induce expression of c-fos and c-jun, proto-oncogenes known to promote cell cycle progession and tissue hyperplasia (7). It was then found that the CagA protein activates SHP2, a tyrosine phosphatase that activates pro-mitotic Ras-MAPK signaling pathways (5). Because constitutive SHP2 signaling can initiate apoptosis, CagA can attenuate its own activity by activating CSK, a negative regulator of the SRC-family kinases that initially activate CagA upon host cell entry. The presence of CagA in gastric cells also leads to an elongated cell shape called the "hummingbird phenotype," a type of cell morphology that often indicates transformation.
The CagA bacterial oncoprotein also disrupts Wnt signaling, an important pathway involved in cell cycle regulation (8). Overactivation of beta-catenin, a signal transduction molecule regulated by the Wnt pathway, is a common feature in tumor transformation (9). Beta-catenin activity is normally inhibited by sequestration of beta-catenin molecules into E-cadherin complexes (10). The CagA oncoprotein competitively binds to E-cadherin, replacing beta-catenin from the complex and releasing it from suppression. Beta-catenin can then translocate to the nucleus to induce transdifferentiation of gastric cells into intestinal cells and initiate hyperplasia. However, the contribution of CagA to hyperproliferation is complicated by the fact that CagA also activates p21, a molecule that enforces cell cycle arrest. Whether or not CagA pushes gastric cells through the cell cycle would have to take into account the balance between inhibitory p21 and pro-growth Ras-MAPK and dysregulated Wnt signaling.
Other Oncogenic Bacteria
In addition to H. pylori, numerous other infectious bacteria, as well as commensal gut flora, display oncogenicity. The advent of next-generation sequencing has been crucial in assessing the diverse community of bacteria that colonize the human large intestine. Of the greater than 1000 bacterial species that populate the colon, some are found to selectively and consistently colonize colorectal tumor samples. Research is underway to determine if the tumor-concentrated bacterial species are drivers for tumorigenesis or if they are passengers which benefit from an altered microenvironment (11).
One such driver bacteria is the enterotoxigenic Bacteroides fragilis (ETBF), which secretes a pro-inflammatory toxin that rapidly and indirectly cleaves E-cadherin, a structural and tumor-suppressing protein. In mouse experiments, ETBF colonization has been found to significantly increase colonic tumor formation (12).
The "Alpha-bug hypothesis" states that members of the microbiome are directly oncogenic and act as major drivers of transformation by remodelling the human tissue landscape. This process is likely to occur in human colonic epithelial cells; however, it may take 20-40 years for sufficient mutations to produce a carcinoma (12).
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