April 18, 2003

Cell talk focus of VICC study

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Dr. Robert J. Coffey

Cell talk focus of VICC study

Dr. Jason D. Morrow

Dr. Jason D. Morrow

The supporting cells of the colon may contribute to cancer by making a substance that in turn prevents the neighboring epithelial cells lining the colon from dying when they are supposed to, Vanderbilt scientists report.

The finding, published in the April 15 issue of the journal Cancer Research, highlights the importance of cell-to-cell communication in cancer development and progression, and it suggests a new way to intervene in the process.

The work also sheds more light on how the enzyme cyclooxygenase-2 contributes to colorectal cancer. COX-2 has been implicated in numerous studies, including landmark work at Vanderbilt, as a leading culprit in colorectal and other cancers. However, its role and that of its prostaglandin products are not fully understood.

In this work, the researchers found that the stromal cells produce a prostaglandin called prostacyclin and demonstrate that it protects the neighboring epithelial cells from apoptosis, or programmed cell death.

“These stromal cells make the one prostaglandin that the epithelial cells don’t make, and this prostaglandin helps ensure the epithelial cells’ survival,” said Dr. Robert J. Coffey, Ingram Professor of Cancer Research and professor of Medicine and Cell & Developmental Biology. The work is the result of collaboration between the research teams of Coffey and Dr. Jason D. Morrow, F. Tremaine Billings Professor of Medicine. Their work has focused on better understanding the role of COX-2 and prostaglandins in cancer.

The researchers previously reported that colon epithelial cells make a number of COX-2-produced prostaglandins but not prostacyclin. In this work, they found that the stromal, or supporting, cells produce significant amounts of prostacyclin.

These cells were mixed in culture with a colon cancer (epithelial) cell line that makes COX2 but does not produce prostacyclin; the investigators noted a markedly reduced rate of apoptosis, or programmed cell death. They also were able to reverse this effect by adding an inhibitor of COX-2 and to restore it by adding a prostacyclin analogue.

This finding may be particularly important because it appears that at least early in the cancer process, COX-2 is chiefly expressed in the stromal cells. Blocking prostacyclin’s protective effect at that stage might prevent colorectal cancers from developing and becoming established.

In addition, the researchers found 50 times greater levels of prostacyclin in stromal cells from patients with hereditary nonpolyposis colorectal cancer (HPNCC) than in those from patients with sporadic colorectal cancer. HPNCC predisposes patients to colorectal cancer because an inherited DNA mutation makes the epithelial cells in the colon more genetically unstable and therefore more prone to malignant changes. The researchers suggest that an overabundance of prostacyclin may allow initiated cells to escape programmed cell death and become fully malignant.

The next step in the research will be to better understand the mechanism through which prostacyclin exerts is anti-apoptotic influence, Morrow said. Another subject of future investigation will be what prompts the stromal cells to produce COX-2 in the first place, whether it’s a normal cellular function or an early step in the cancer process.

Morrow noted that the findings result from an ongoing collaboration between himself and Coffey that spans nearly a decade. “It really highlights the type of interaction that Vanderbilt is famous for, two people from diverse backgrounds coming together to solve problems of biologic importance,” he said.

Morrow’s and Coffey’s collaborators include N. Shane Cutler, Ramona Graves-Deal Bonnie LaFleur, Zhenqiang Gao, Bruce M. Boman, Erin Terry and Robert Whitehead.

The work was funded by grants from the National Cancer Institute, including a Specialized Program of Research Excellence (SPORE) in gastrointestinal cancer grant, as well as a Burroughs Welcome Clinical Scientists Award in Translational Science.