An oral bacterium, Fusobacterium nucleatum, was recognized years ago as a promoter of colon cancer. But exactly how F. nucleatum worsened colon cancer remained unknown. Now, thanks to research carried out at Columbia University, the bacterium’s cancer-exacerbating ways are better understood. Basically, the bacterium provides the second hit in a two-hit mechanism, completing a feedback loop that amplifies cancer signaling.
The Columbia scientists, led by Yiping W. Han, PhD, professor of microbial sciences, followed up on a finding that they had uncovered earlier. They had discovered that the bacterium makes a molecule called FadA adhesin, triggering a signaling pathway in colon cells that has been implicated in several cancers. They also found that FadA adhesin stimulates the growth of cancerous cells, not that of healthy cells.
“We needed to find out why F. nucleatum seems to interact only with cancerous cells,” Han pointed out.
Working with cell cultures, the researchers found that noncancerous colon cells lack Annexin A1, a protein that stimulates cancer growth. The researchers then confirmed both in vitro and later in mice that disabling Annexin A1 prevented F. nucleatum from binding to the cancer cells, slowing their growth. The researchers also discovered that F. nucleatum increases production of Annexin A1, attracting more of the bacteria.
The implications of these findings were discussed in a paper (“Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/β‐catenin modulator Annexin A1”) that appeared March 3 in EMBO Reports.
“A positive feedback loop between FadA and Annexin A1 is identified in the cancerous cells, absent in the noncancerous cells,” the article’s authors wrote. “We therefore propose a ‘two‐hit’ model in colorectal carcinogenesis, with somatic mutation(s) serving as the first hit, and F. nucleatum as the second hit exacerbating cancer progression after benign cells become cancerous.”
The two-hit model, the Columbia team suggested, extends the “adenoma‐carcinoma” model of cancer progression and identifies microbes such as F. nucleatum as cancer “facilitators.”
Colon cancer, the second leading cause of cancer death in the United States, is well known to result from genetic mutations that typically accumulate over the course of a decade. “Mutations are just part of the story,” Han emphasized. “Other factors, including microbes, can also play a role.”
To reinforce this point, Han’s team scrutinzed an RNA-sequencing dataset, available through the National Center for Biotechnology Information, of 466 patients with primary colon cancer. This dataset was examined to evaluate the expression of Annexin A1, which had not previously been recognized as a modulator of Wnt/β‐catenin signaling.
“Annexin A1 is specifically expressed in proliferating colorectal cancer cells and involved in activation of Cyclin D1,” the researchers determined. “Its expression level in colon cancer is a predictor of poor prognosis independent of cancer stage, grade, age, and sex.”
Going forward, the researchers intend to exploit the findings derived from their work on F. nucleatum, a bacterium best known for its role in tooth decay, but now known to promote colon cancer through a specific signaling mechanism. For example, the researchers are working to develop Annexin A1 as a biomarker for more aggressive cancers and as a potential target for developing new treatments for colon and other types of cancer.
