Apr 4 2006
Researchers have known for years that the enzyme MMP-9 plays a key role in the spread of colorectal cancer. Now, scientists at Jefferson Medical College in Philadelphia have found out how the enzyme helps initiate the process, known as metastasis.
Their discovery of a new molecular mechanism by which MMP-9 promotes cancer spread may provide a new target at which to aim anti-metastasis drugs.
MMP-9--matrix metalloproteinase 9--is a member of a family of enzymes that is instrumental in freeing cells from surrounding tissue, enabling them to move and spread. Scientists have long known that MMP-9 is essential to metastasis, one of several factors that allow cells to invade nearby tissue and migrate to other tissues and organs in the body. MMP-9, which is produced by normal stromal cells in colorectal tumors, has been linked to colorectal cancer spread to the lung and liver.
Reporting in the current issue of Clinical Cancer Research, a journal of the American Association for Cancer Research, GianMario Pitari, M.D., Ph.D., assistant professor of pharmacology and experimental therapeutics at Jefferson Medical College of Thomas Jefferson University and at Jefferson's Kimmel Cancer Center, and his co-workers compared MMP-9 expression in colorectal cancer tumors and normal adjacent tissue in the laboratory. They found that MMP-9 is overexpressed in the tumor, which they expected.
What they did not expect to find was that MMP-9 was expressed equally by both cancer and stromal cells in the tumor. What's more, they found that the cancer cells were the source of the MMP-9 that kick-started the metastatic process.
Dr. Pitari and his group also showed that by blocking the enzyme, the colorectal cancer cell cannot metastasize to other tissue.
"We showed that MMP-9 is highly expressed by the colon cancer cell, which has metastasized, and is fundamental to permit tumor cell proliferation to distant sites," Dr. Pitari says. "In addition to stromal cells, the tumor cell itself is a good source of MMP-9 and in fact, is doing the seeding of the colon cancer, promoting metastasis. No one has ever shown this particular mechanism. The current paradigm suggests that mainly the stromal cell within the tumor is the major MMP-9 producer in colorectal tumors. Surprisingly, MMP-9 is key to initiating metastasis.
"This mechanism could be a new target for drugs to prevent metastasis in colon cancer," he says.
Dr. Pitari explains that the precise mechanism by which MMP-9 and MMPs in general mediate metastasis was not clearly known, and this lack of understanding of the process was part of the reason previously attempted therapies failed. According to Dr. Pitari, scientists have tried to design inhibitors of MMP-9, but drug trials have failed to help patients with colorectal cancer live any longer. These enzymes have other physiological functions, particularly in the immune system.
The research team is now seeking ways to target the tumor cell specifically and inhibit MMP-9. They would like to find ways to block the production and release of MMP-9 by the colorectal tumor without targeting the stromal cell which, as it turns out, might actually have beneficial anti-tumor effects.
"We are investigating how we can block production and release of MMP-9 specifically by the tumor cell without targeting the stromal cell and its MMP-9, which might have beneficial effects in preventing metastasis," Dr. Pitari notes.
"MMPs are a fertile area to target in many other cancers as well. Going after the tumor cell and a specific mechanism in the tumor cell that mediates metastasis could be a key to follow in the future to develop an effective strategy to prevent metastasis."