Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer

Reviewed by Dr. Branden Tarlow
Bullman S, et al. Science, 2017 Dec 15. 356:6369, 1443-1448

SUMMARY
Fusobacterium nucleatum is a common constituent of the intestinal microenvironment and has recently been identified in gene sequencing studies of colorectal cancer samples but has unclear clinical significance. Here, Bullman and colleagues studied colorectal cancer patient tissue samples and found that Fusobacterium and other bacterium were present not only in the primary tumors but also in distant metastases in 9 of 11 patients. The bacteria in the metastatic tumors were nearly identical in sequence and species as the primary tumor, suggesting that the bacteria traveled with primary tumor cells, likely within endosomal compartments. In a separate cohort of primary colorectal cancers (n = 77 patients, 45% Fusobacterium-positive), however, the authors found no association between Fusobacterium and subsequent clinical recurrence. Finally, patient-derived xenografts were established in mice from primary Fusobacterium-positive colorectal cancer cells. Antibiotic treatment of mice with metronidazole (active against Fusobacterium) but not erythromycin (inactive against Fusobacterium) decreased tumor growth, suggesting a causal role for the bacteria in tumor growth and maintenance.

COMMENTARY
This study adds to the complex understanding of the tumor microenvironment and role of the normal intestinal microenvironment on tumorigenesis. It raises the possibility that Fusobacterium necrophorum interacts with tumor cells to play an important role in the initiation and progression of colorectal cancers. Recent clinical observations have associated increased tumor levels of Fusobacterium with less T-cell infiltration, advanced disease stage and poorer patient survival. A separate study linked fusobacterial lipopolysaccharide to activation of a key growth signaling pathway in cancer cells (1). But this raises more questions: does antibiotic treatment change the microbiota and alter the risk of colon tumor initiation? Will there be a role for narrow-spectrum antibiotics in the treatment or prevention of colorectal cancer? Several limitations of the study were that it did not replicate an earlier report that Fusobacterium load predicted clinical outcomes like recurrence after resection (2). Moreover, if bacteria promoted clonal selection of the tumor it is unclear why bacteria were 10-100x lower in distant metastases compared with primary tumors. Nevertheless, Bullman et al have put forth a biologically plausible argument that the intestinal microbiota regulates immune function and cell growth outside of the gut—and raise hopes that the causal relationship identified in mice will be replicated in the clinical studies.

REFERENCES
1. Yang Y et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signalling to neulcear factor-kB, upregulating expression of microRNA-21. Gastroenterology 2017; 152:851-866.
2. Yu T et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 2017; 170:548-563.

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