Dec. 21, 1999 A research team based at the Massachusetts General Hospital (MGH) has shown that a natural factor called thrombospondin-2 (TSP-2) inhibits the development of certain tumors in a mouse model by preventing the development of blood vessels, a process called angiogenesis. TSP-2 now joins a growing list of anti-angiogenesis factors being studied and in some instances tested as possible anti-cancer drugs. The report from the MGH Cutaneous Biology Research Center (CBRC) appears in the Dec. 21 issue of Proceedings of the National Academy of Sciences.
"We have found a natural factor that inhibits angiogenesis in normal tissues and, when reintroduced into tumor cells, stops tumor growth," says Michael Detmar, MD, who led the study. Detmar notes that some of the other anti-angiogenesis factors currently being studied do not appear to be involved in normal blood vessel development but instead are produced when other substances in the body break down. "We believe that TSP-2 is part of a natural protein system designed to prevent the development of malignant tumors," he adds.
TSP-2 is one of a group of proteins that help regulate the proliferation and development of several types of cells. It is structurally similar to thrombospondin-1 (TSP-1), a known angiogenesis inhibitor. Although the two proteins are produced at different times during development and in different tissues, both appear at high levels in developing blood vessels, suggesting an important role in the regulation of angiogenesis. While TSP-1 had previously been shown to inhibit angiogenesis and tumor growth, TSP-2's exact biological role had been unclear. The current study not only verifies TSP-2's activity in suppressing tumor growth and angiogenesis, it also shows that expression of both proteins completely stopped growth of the tumors studied in this project.
The researchers introduced TSP-2 DNA into cultured cells from human squamous cell carcinomas - tumors that do not normally produce TSP-2 - and injected the cells into the skin of immune deficient mice. As a control, another group of mice received injections of unaltered human squamous cell carcinoma cells. While the unaltered cells quickly grew into tumors, tumors from the cells induced to produce TSP-2 grew very slowly and also showed reduced angiogenesis.
The suppression of tumor growth resulting from TSP-2 production was significantly greater than that seen in earlier studies of the effect of TSP-1 production - 90 percent reduction in tumor growth versus 40 to 50 percent. In addition, squamous cell carcinoma cells into which genes for both TSP-2 and TSP-1 were introduced completely failed to develop into tumors.
While they are encouraged by the study results, the researchers stress that many questions need to be answered about TSP-2's possible role as a cancer-fighting agent. Among these are exactly how the protein operates on a molecular level and whether the same anti-tumor effect is seen with other types of cancer. The researchers already have found a similar effect in human malignant melanoma. Also required are practical methods of inducing TSP-2 production in tumor cells. Possible strategies may include gene therapy approaches, introduction of small molecules that stimulate secretion of TSP-2, or bio-engineered implants that could deliver the protein to the area of a tumor.
Supporters of this study include the National Cancer Institute, the National Institutes of Health and the American Cancer Society. The study's co-authors are first author Michael Streit, MD, Lucia Riccardi, Paula Velasco, and Thomas Hawinghorst, MD, of the MGH CBRC; Lawrence Brown, MD, of Beth Israel Deaconess Medical Center; and Paul Bornstein, MD, of the University of Washington in Seattle.
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