Gut Microbes Create a Liver Premetastatic Niche in Colorectal Cancer

The gut vascular barrier, which restricts access of gut microbes and large molecules to the bloodstream, can be compromised by some enteric bacteria. Although colorectal cancer is associated with disruptions to the microbial composition of the gut, how these alterations may influence the gut vascular barrier—and, potentially, cancer progression and spread—remain unknown. Bertocchi and colleagues investigated this, beginning with a retrospective analysis of colorectal cancer outcomes based on gut vascular barrier permeability as assessed using plasmalemma vesicle-associated protein-1 (PV-1) levels. This revealed that, although PV-1 positivity in CD31⁺ colon endothelial cells was not prognostic with regard to overall survival, an abundance of PV-1^hi cells in primary colorectal cancer tumors was associated with tumor recurrence and distant metastasis independent of other risk factors (e.g., lymph node involvement at diagnosis). The presence of a large number of cells that highly expressed PV-1 in the primary tumors of patients with colorectal cancer was associated with a greater number of bacteria in metastatic lesions in the liver, particularly around SOX9⁺ cancer cells rather than CD31⁺ blood vessel cells. Additionally, cells from PV-1^hi primary tumors had a greater propensity of metastasize to the liver than cells from PV-1^lo primary tumors, which metastasized equally to the liver and lungs. Further in vivo investigation revealed that these tumor-associated bacteria colonized the liver prior to liver metastasis in colorectal cancer, forming an inflammatory premetastatic niche that may be favorable for liver metastatic seeding. Importantly, in the mouse colorectal cancer model, isolation of bacteria from primary colon tumors and liver revealed that both sites were substantially colonized by Escherichia coli strain C17, which appeared to disrupt the gut vascular barrier via their type III secretion system, and this colonization preceded the formation of metastases. In summary, this study shows that the presence of certain bacteria in the gut may contribute to gut vascular barrier dysfunction, enabling bacteria to establish residence in the liver and form a premetastatic niche favorable for metastatic colorectal cancer cells.

Bertocchi A, Carloni S, Ravenda PS, Bertalot G, Spadoni I, Cascio AL, et al. Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver. Cancer Cell 2021 Apr 1 [Epub ahead of print].

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