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Oncogenes and Angiogenesis: Down-regulation of Thrombospondin-1 in Normal Fibroblasts Exposed to Factors from Cancer Cells Harboring Mutant Ras

¹ Henderson Research Centre and ² Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; ³ Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁴ Department of Biochemistry, University of Washington, Seattle, Washington

Requests for reprints: Janusz Rak, Hamilton Civic Hospitals Research Centre, McMaster University, Room 216, Hamilton, Ontario, Canada L8V 1C3. Phone: 905-527-2299; Fax: 905-575-2646; E-mail: jrak{at}thrombosis.hhscr.org.

The onset of angiogenesis in cancer often involves down-regulation of endogenous angiogenesis inhibitors, of which thrombospondin-1 (TSP-1) is a paradigm. As this effect is thought to occur under the influence of transforming genetic lesions (e.g., expression of the mutant ras oncogene), its nature is regarded as intrinsic to cancer cells themselves. Here, we show that ras-transformed cancer cells can also induce TSP-1 down-regulation in their adjacent nontransformed stromal fibroblasts, but not in endothelial cells, in a paracrine and distance-dependent manner. Indeed, several H-ras-expressing fibrosarcoma (528ras1, B6ras, and NIH3T3Ras) and carcinoma (DLD-1 and IEC18Ras3) cells were found to release soluble factors capable of suppressing TSP-1 protein, mRNA, and promoter activity in nontumorigenic, immortalized dermal fibroblastic cell lines in culture (e.g., in fibroblasts expressing enhanced green fluorescent protein/TSP-1 reporter). This effect was abrogated in Id1–/– fibroblasts. At least two low molecular weight (<3 kDa), heat-labile, and trypsin-resistant mediators of TSP-1 suppression were found to be released from 528ras1 cells. Their effects on normal fibroblasts were inhibited (albeit to different extents) by pertussis toxin and, in one case, by dimethylsphingosine, none of which affected TSP-1 expression by 528ras1 cells. Collectively, our study suggests that the effect of mutant ras on tumor neovascularization is not limited to changes in angiogenic properties of cancer cells themselves. Rather, mutant ras, through a different signaling mechanism, may modulate the properties of the adjacent normal stroma, thus eliciting a proangiogenic field effect.

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