NEW YORK, NY (March 4, 2019)--Researchers at the Columbia University College of Dental Medicine have determined how F. nucleatum -- a common oral bacteria often implicated in tooth decay -- accelerates the growth of colon cancer. The study was published online in the journal EMBO Reports.

Why it matters

The findings could make it easier to identify and treat more aggressive colon cancers. It also helps explain why some cases advance far more quickly than others, thanks to the same bacteria found in dental plaque.

Background

Colon cancer is the second leading cause of cancer death in the U.S. Researchers have long known that the disease is caused by genetic mutations that typically accumulate over the course of a decade. "Mutations are just part of the story," says study leader Yiping W. Han, PhD, professor of microbial sciences at Columbia University's College of Dental Medicine and Vagelos College of Physicians & Surgeons. "Other factors, including microbes, can also play a role."

Scientists have also demonstrated that about a third of colorectal cancers are associated with a common oral bacterium called F. nucleatum. Those cases are often the most aggressive, but nobody knew why. In a prior study, Han's research team 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 only stimulates the growth of cancerous cells, not healthy cells. "We needed to find out why F. nucleatum only seemed to interact with the cancerous cells," says Han.

What the study found

In the current study, the researchers found in cell cultures that noncancerous colon cells lack a protein, called Annexin A1, which stimulates cancer growth. They 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. "We identified a positive feedback loop that worsens the cancer's progression," says. Han. "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."

Clinical implications

The researchers then looked at an RNA-sequencing dataset, available through the National Center for Biotechnology Information of 466 patients with primary colon cancer. Patients with increased Annexin A1 expression had a worse prognosis, regardless of the cancer grade and stage, age, or sex.

Next steps

The researchers are currently looking for ways 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.

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More details

Yiping Han, PhD, is a professor of microbial sciences in dental medicine at the Columbia University College of Dental Medicine and of microbiology and immunology at Columbia University Vagelos College of Physicians & Surgeons.

The study is titled, "Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/ß-catenin modulator Annexin A1."

The other contributors are Mara Roxana Rubinstein (Columbia), Jung Eun Baik (Columbia), Stephen M. Lagana (Columbia), Richard P. Han (The Horace Mann School, Bronx, NY), William J. Raab (Columbia), Debashis Sahoo (University of California San Diego, San Diego, CA), Piero Dalerba (Columbia), and Timothy C. Wang (Columbia).

The study was funded by grants from the National Institutes of Health (RO1CA192111, RO1DE014924, RO1DE023332, and P30 CA013696). Dr. Dalerba receives royalties and/or stocks from OncoMed Pharmaceuticals Inc., Quanticel Pharmaceuticals Inc. (now a fully owned subsidiary of Celgene) and Forty Seven Inc. as a coinventor of several patents and patent applications. The other authors declare no financial or other conflicts of interest.

About Columbia University College of Dental Medicine

Columbia University College of Dental Medicine (CDM), one of the nation's first dental schools, educates general dentists and specialists to practice dentistry as the oral health specialty of medicine. CDM provides comprehensive, precision care to over 30,000 patients each year through more than 130,000 visits, making CDM the largest source of oral healthcare to underserved upper Manhattan communities. A centerpiece of the school's offerings is the Center for Precision Dental Medicine, a clinic that will personalize care and education through big data and first-of-its-kind technology. Other programs bring oral healthcare to local schools, seniors, and community centers. For more information, visit dental.columbia.edu.

About Columbia University Irving Medical Center

Columbia University Irving Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the Vagelos College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Irving Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cuimc.columbia.edu or columbiadoctors.org.