Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo

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 an...

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Bibliographic Details
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
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Summary: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.
ISSN:0021-9738
DOI:10.1172/jci3793