Colon cancer is the second leading cause of cancer death in America. A third of those colorectal cancers – the most aggressive of the cases – are associated with a common oral bacterium called F. nucleatum. This connection and the fact that the disease is caused by genetic mutations that typically accumulate over the course of a decade has been known. What the scientists didn’t know was why.
Yiping W. Han, Ph.D., professor of microbial sciences at Columbia University’s College of Dental Medicine and Vagelos College of Physicians & Surgeons, and leader of the study said:
“Mutations are just part of the story. Other factors, including microbes, can also play a role.”
Fusobacterium nucleatum, or F. nucleatum, is a common bacteria. It is best known for its role in the accumulation of periodontal plaque. Han’s research team discovered (in a previous study) that F. nucleatum enhances colorectal cancer growth by triggering a signaling pathway in colon cells. It does this through a molecule called FadA adhesin. This molecule, FadA adhesin, only stimulates the growth of cancerous cells, not healthy cells.
This discovery led to more questions and another study. The researchers needed to find out exactly why this specific process seemed to only stimulate the growth of cancer cells. Yiping Han, lead on the new study from the Columbia University College of Dental Medicine, said:
“We needed to find out why F. nucleatum only seemed to interact with the cancerous cells.”
In the new study, the researchers found that the cancer stimulator appears to be a specific protein called Annexin A1. This protein is only expressed by cancerous colon cells, and it stimulates cancer growth. They also found that FadA adhesin, the molecule expressed by F. nucleatum, stimulates cancer cell growth via interaction with Annexin A1. This interaction creates a feedback loop between the bacteria and the cancer cell, which explains why F. nucleatum only enhances cancer cell growth and doesn’t affect healthy cells.
Han said:
“We identified a positive feedback loop that worsens the cancer’s progression. We propose a two-hit model, where genetic mutations are the first hit. F. nucleatum serves as the second hit, accelerating the cancer signaling pathway and speeding tumor growth.”
They then confirmed (both in vitro and later in mice) that it was possible to slow the growth of cancer cells by disabling Annexin A1 and thus preventing F. nucleatum from binding to the cancer cells.
Next, to verify their results, the researchers looked at an RNA-sequencing dataset of 466 patients with primary colon cancer. The dataset was available through the National Center for Biotechnology Information Patients. What they found was that the people with increased Annexin A1 expression had a worse prognosis, regardless of the cancer grade and stage, age, or sex. The new study was published in the journal EMBO Reports.
Conclusion
This research reveals a key mechanism that helps explain why some cancers tend to progress more rapidly in specific patients. Their findings should help clinicians better identify patients who suffer from faster-growing and more aggressive cancers by checking for this valuable biomarker. Furthermore, it could open the door to new treatments to slow cancer growth by targeting this particular pathway. The researchers are currently looking into all these options.
