Study shows that a key protein appears to enable spread of melanoma to the small intestine

A study by researchers at the John Wayne Cancer Institute at Saint John's Health Center has shown that a receptor protein found on melanoma cells appears to facilitate the disease's spread to the small intestine.

The study, published in the Feb. 1, 2008, issue of Clinical Cancer Research, also suggests that merging of the protein, called CCR9, with the CCL25 protein, which is known to play a role in the development of disease-fighting white blood cells, may help to explain the high incidence of melanoma metastasis to the lower bowel.

Melanoma is the most serious type of skin cancer, with more than 53,000 people in the U.S. diagnosed each year. Over the past three decades the percentage of people in the U.S. who develop this form of cancer has more than doubled. The disease is unique in that it metastasizes to the small intestine, where the spread of any other form of cancer is uncommon.

The study, “Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine,” was one of the largest of its kind to investigate the spread of melanoma to the gastrointestinal tract. It used various techniques, such as molecular biology, immunostaining and laboratory functional studies, to assess tumors for the two proteins; CCL25 is important because it often is produced in the small intestine—particularly during inflammation.

Results of the study showed CCR9 in 88 of 102 metastatic melanomas from the small intestine; in contrast, none of the 96 melanomas from other metastatic organ sites showed the CCR9 protein. Laboratory studies performed on CCR9-positive melanoma cells demonstrated metastatic properties in response to CCL25 that could be inhibited by specific chemical substances.

“We assessed tumor cells in the small intestine for CCR9 and demonstrated it with high significance compared with metastasis to other organs,” Hoon said. “Others, including our group, have demonstrated that certain cancers frequently spread to specific distant organs, often due to vascular drainage patterns, certain properties of organs, and anatomical location of the tumor origin site. What's unique here is that melanomas on or affecting the skin occur at multiple anatomical sites on the body and there's no direct vascular connection to the small intestine, yet the melanoma cells released from the primary tumor are attracted to this organ site.”

“The cell homing process involved is a well-developed biologic mechanism by which immune and inflammatory white blood cells move to specific sites during infection, inflammation or injury. The CCR9 receptor is revealed differentially via blood T lymphocytes to the small intestines. During inflammation of the small intestine, CCR9-positive lymphocytes are attracted. It appears that melanoma cells have hijacked the biological process of T lymphocytes to travel to the small intestine,” Hoon said.

“This is a unique demonstration of signaling, or the attraction of melanoma to a specific distant organ site,” Hoon said, likening it to the classic Seed and Soil concept of metastatic tumor spread developed by Stephen Pagett, whereby an attracting signaling factor—in this case the CCR9—facilitates metastasis. “If we can identify patients' melanomas that have these specific receptors, then we'll know they have a high propensity to metastasize to the small intestine.”

He added that treatment targeting the CCR9 receptor may one day help to prevent the spread of melanoma to the small intestine.

Funding for this study was provided by the Martin H. Weil Foundation at JWCI, the National Institutes of Health, and the National Cancer Institute.

Since 1981, the Wayne family has committed the John Wayne name to groundbreaking cancer research and education in memory of the famed actor, who died of cancer. The John Wayne Cancer Institute at Saint John's Health Center has received worldwide acclaim for advances in melanoma, breast cancer and rectal cancer as well as immune therapy for cancer. Other areas of research include studies on gastrointestinal cancer. The JWCI's unique ability to rapidly turn laboratory scientific research into applied translational approaches to treatment and detection provides hope to cancer patients from around the globe.

Farin F. Amersi, Alicia M. Terando, Yasufumi Goto, Richard A. Scolyer, John F. Thompson, Andy N. Tran, Mark B. Faries, Donald L. Morton, and Dave S.B. Hoon, “Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine,” Clinical Cancer Research, Volume 14, Issue 3, February 1, 2008.