Polypeptide growth factors contribute to the development and maintenance of normal tissues and are essential for the growth and metastasis of solid tumors. During tumor progression these factors function as autocrine stimulators of tumor cells and/or serve to recruit stromal tissue and blood supply to the expanding tumor. In particular, tumor-induced angiogenesis appears to be significant not only for local tumor growth but also for metastasis to distant organ sites. We purified several years ago the heparin-binding growth factor pleiotrophin (PTN) from the supernatants of human breast cancer cells and demonstrated that PTN can serve as an angiogenesis factor. We found the gene expressed in a number of human tumor cell lines as well as in human tumor tissues. Here we present different approaches to inhibit production and function of this growth factor. Finally we discuss how the experience from this growth factor can be applied to improve our understanding of the role of other factors thought to contribute to tumor angiogenesis.
In the present study, we report that staurosporine, a known PKC inhibitor, enhanced in vitro angiogenesis. Endothelial cells plated in a three-dimensional matrix formed cords and enclosed structures within 4-6 hours. The cells in cord structures became elongated during the subsequent incubation. Tube formation was confirmed by confocal microscopy. Addition of VEGF enhanced the early responses of endothelial cells, leading to enhanced formation of cords. Staurosporine unexpectedly also enhanced the early endothelial responses, leading to faster alignment of cells and assembly into tube-like structures. At concentrations inhibitory to endothelial cell PKC activity, staurosporine produced 91% and 203% increases in the number of cords and the enclosed structures, respectively, as compared to the controls. Other selective inhibitors of PKC did not stimulate in vitro angiogenesis in the absence or presence of VEGF. Further investigation showed that inhibition of PI-3 kinase and Raf-1 significantly reduced the effects of staurosporine. Staurosporine-induced in vitro angiogenesis required integrins alpha2 and alphavbeta3 and was associated with significantly enhanced FAK phosphorylation. These data indicate that staurosporine enhances in vitro angiogenesis by a means unrelated to its PKC inhibition. The data suggest that enhancement of in vitro angiogenesis by staurosporine involves integrin-mediated signaling, including the stimulation of FAK phosphorylation.
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