Editors' ChoiceCancer

Bacterial-induced transformation

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Sci. Signal.  30 Jun 2015:
Vol. 8, Issue 383, pp. ec176
DOI: 10.1126/scisignal.aac8704

The intracellular human pathogen Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, and chronic carriers of this bacterium have an increased risk for developing gallbladder cancer. Scanu et al. tested whether Salmonella infection could provoke cancer formation in mice with genetic factors predisposing them to cancer. Infection with Salmonella enterica serovar Typhimurium (S. Typhimurium) promoted the formation of tumors in colons of Apc+/min mice, which are susceptible to developing intestinal cancers. S. Typhimurium infection also stimulated the production of new organoids in the absence of exogenous growth factors from individual cells isolated from murine gallbladder organoids derived from mice lacking the tumor-suppressing activity of TP53 (also known as p53). Comparing the effects of S. Typhimurium or S. Typhi infection on wild-type mouse embryo fibroblasts (MEFs) and MEFs from mice with genetic modifications that disrupted the tumor-suppressing activity of TP53 or resulted in the overexpression of the oncoprotein c-MYC or both indicated that infection specifically enhanced anchorage-independent growth of the MEFs with both TP53 inactivation and overexpression of c-MYC and enabled these infected cells to produce solid tumors when implanted into mice, even when the cells had been treated with antibiotics prior to injection. Some virulence factors injected into host cells by S. Typhimurium promote the activity of the kinase AKT or stimulate mitogen-activated protein kinase (MAPK) signaling. A strain of S. Typhimurium lacking these virulence factors did not promote growth of MEFs lacking TP53 activity and overexpressing c-MYC in soft agar as efficiently as did wild-type S. Typhimurium. Low concentrations of chemical inhibitors of MAPK and AKT activity prevented anchorage-independent growth of infected MEFs that lacked TP53 activity and overexpressed c-MYC. Expression of constitutively active forms of AKT or the MAPKK MEK promoted anchorage-independent growth of MEFs lacking TP53 activity and overexpressing c-MYC, but not of MEFs only lacking TP53 activity. The persistence of the transformed phenotype after eradication of the bacteria with antibiotics required sustained AKT and MAPK signaling. These results may explain the link between bacterial infection and cancer in genetically predisposed individuals (see Boccellato and Meyer).

T. Scanu, R. M. Spaapen, J. M. Bakker, C. B. Pratap, L.-E. Wu, I. Hofland, A. Broeks, V. K. Shukla, M. Kumar, H. Janssen, J. Y. Song, E. A. Neefjes-Borst, H. Te Riele, D. W. Holden, G. Nath, J. Neefjes, Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma. Cell Host Microbe 17, 763–774 (2015). [PubMed]

F. Boccellato, T. F. Meyer, Bacteria moving into focus of human cancer. Cell Host Microbe 17, 728–730 (2015). [PubMed]