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From the Department of Pathology,* Division of Tumor Biology and Angiogenesis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; the Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts; and the Department of Gynecology and Obstetrics, Georg-August-University of Goettingen, Goettingen, Germany
In the present study, the type-1 repeats of thrombospondin-1 (TSP-1) were transfected into A431 cells. Expression of all three type-1 repeats (3TSR) and expression of just the second type-1 repeat containing the transforming growth factor (TGF)-ß activating sequence KRFK (TSR2 + KRFK) significantly inhibited in vivo tumor angiogenesis and growth in nude mice. These tumors expressed increased levels of both active and total TGF-ß. A431 cells expressing the second type-1 repeat without the KRFK sequence (TSR2 – KRFK) produced tumors that were slightly larger than the 3TSR and TSR2 + KRFK tumors. These tumors expressed elevated levels of active TGF-ß but levels of total TGF-ß were not different from control tumors. Injection of the peptide, LSKL, which blocks TSP-1 activation of TGF-ß, reversed the growth inhibition observed with cells expressing TSR2 + KRFK to a level comparable to controls. Various residues in the WSHWSPW region and the VTCG sequence of both TSR2+/– KRFK were mutated. Although mutation of the VTCG sequence had no significant effect on tumor growth, mutation of the WSHWSPW sequence reduced inhibition of tumor growth. These findings suggest that the inhibition of tumor angiogenesis and growth by endogenous TSP-1 involves regulation of both active and total TGF-ß and the sequences KRFK and WSHWSPW in the second type-1 repeat.
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