Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo

• Published in: The Journal of clinical investigation 1998-10, Vol.102 (8), p.1599-1608
• Main Authors: Sharma, B, Handler, M, Eichstetter, I, Whitelock, J M, Nugent, M A, Iozzo, R V
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma - drug therapy; Colonic Neoplasms - drug therapy; DNA, Antisense - therapeutic use; Fibroblast Growth Factor 10; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Gene Expression; Growth Substances - metabolism; Heparan Sulfate Proteoglycans; Heparitin Sulfate - biosynthesis; Heparitin Sulfate - genetics; Heparitin Sulfate - metabolism; Humans; Melanoma, Experimental - drug therapy; Mice; Neoplasm Transplantation; Neoplasms, Experimental - drug therapy; Neovascularization, Pathologic - drug therapy; Protein Binding; Proteoglycans - biosynthesis; Proteoglycans - genetics
• ISSN: 0021-9738
• DOI: 10.1172/jci3793

Perlecan, a ubiquitous heparan sulfate proteoglycan, possesses angiogenic and growth-promoting attributes primarily by acting as a coreceptor for basic fibroblast growth factor (FGF-2). In this report we blocked perlecan expression by using either constitutive CMV-driven or doxycycline- inducible antisense constructs. Growth of colon carcinoma cells was markedly attenuated upon obliteration of perlecan gene expression and these effects correlated with reduced responsiveness to and affinity for mitogenic keratinocyte growth factor (FGF-7). Exogenous perlecan effectively reconstituted the activity of FGF-7 in the perlecan-deficient cells. Moreover, soluble FGF-7 specifically bound immobilized perlecan in a heparan sulfate-independent manner. In both tumor xenografts induced by human colon carcinoma cells and tumor allografts induced by highly invasive mouse melanoma cells, perlecan suppression caused substantial inhibition of tumor growth and neovascularization. Thus, perlecan is a potent inducer of tumor growth and angiogenesis in vivo and therapeutic interventions targeting this key modulator of tumor progression may improve cancer treatment.