Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo

被引:154
作者
Sharma, B
Handler, M
Eichstetter, I
Whitelock, JM
Nugent, MA
Iozzo, RV
机构
[1] Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
[3] CSIRO, CRC Cardiac Technol, Sydney, NSW 2070, Australia
[4] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA
关键词
proteoglycans; heparan sulfate; fibroblast growth factor; FGF-2; FGF-7;
D O I
10.1172/JCI3793
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1599 / 1608
页数:10
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