Although genetic factors are essential to the development of colorectal cancer (CRC), the intestinal microbiota were recently recognized as an important environmental contributor. In this issue, Gerold Bongers, Sergio Lira, and colleagues demonstrate for the first time that the microbiota influence site-specific development of tumors in a mouse model of CRC.
HBUS mice express two oncogenic transgenes throughout their intestines—cytomegalovirus chemokine receptor US28 and heparin-binding EGF-like growth factor—but they develop tumors (serrated polyps or SPs) only in the cecum. When the authors treated HBUS mice with broad-spectrum antibiotics they noticed that development of cecal SPs was virtually ablated. Importantly, changing the HBUS microbiome by transferring HBUS embryos into female mice obtained from a different animal vendor also attenuated the development of SPs. Microbiome analysis indicated that antibiotic-mediated attenuation of SPs was correlated with reduced invasion of cecal tissue by bacteria belonging to the Clostridiales/Lachnospiraceae family. Together, these findings link bacterial topology and intestinal barrier defects with site-specific tumor development.
The work of Bongers et al. raises questions about the relationship between bacteria and site-specific cancer development. First, longitudinal analysis of the microbiota in HBUS mice would help define the geographical establishment of microbial niches in relation to tumor development. Similarly, longitudinal assessment of intestinal barrier integrity in HBUS mice would determine whether the barrier defect is the consequence of neoplasia, as observed in a mouse model of colon adenoma, or due to an intrinsic host malfunction that bacteria exploit to promote tumorigenesis.
Interestingly, enrichment of the mucin-degrading bacterium Akkermansia muciniphila in SPs of HBUS mice may strip the mucosa of its protective layer, thereby creating favorable conditions for Clostridiales/Lachnospiraceae invasion into the mucosal tissues with ensuing inflammatory host responses. In the context of dysregulated EGFR signaling in HBUS mice, this situation favors tumor promotion. Experiments using germ-free HBUS mice would help assess this possibility as well as establish the functional interaction between various microbial communities and tumor locations.
In summary, this study adds additional layers of complexity to cancer etiology by highlighting the interplay between host genetics, microbial location, and tumor geography. Whether microbial niche localization influences SP development in humans requires further investigation.
