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Essential Contribution of Tumor-derived Perlecan to Epidermal Tumor Growth and Angiogenesis

Xinnong Jiang, Hinke Multhaupt, En Chan, Liliana Schaefer, Roland M. Schaefer and John R. Couchman

Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama (XJ,JRC); Division of Biomedical Sciences, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom (XJ,HM,EC,JRC); and University of Muenster, Medizinische Poliklinik, Muenster, Germany (LS,RMS)

Correspondence to: John R. Couchman, Biomedical Sciences, Faculty of Medicine, Imperial College London, Exhibition Road, London SW7 2AZ, UK. E-mail: j.couchman{at}imperial.ac.uk

As a major heparan sulfate proteoglycan (PG) in basement membranes, perlecan has been linked to tumor invasion, metastasis, and angiogenesis. Here we produced epidermal tumors in immunocompromised rats by injection of mouse RT101 tumor cells. Tumor sections stained with species-specific perlecan antibodies, together with immunoelectron microscopy, showed that perlecan distributed around blood vessels was of both host and tumor cell origin. Tumor-derived perlecan was also distributed throughout the tumor matrix. Blood vessels stained with rat-specific PECAM-1 antibody showed their host origin. RT101 cells also expressed two other basement membrane heparan sulfate PGs, agrin and type XVIII collagen. Antisense targeting of perlecan inhibited tumor cell growth in vitro, while exogenous recombinant perlecan, but not heparin, restored the growth of antisense perlecan-expressing cells, suggesting that perlecan core protein, rather than heparan sulfate chains from perlecan, agrin, or type XVIII collagen, regulates tumor cell growth. However, perlecan core protein requirement was not related to fibroblast growth factor-7 binding because RT101 cells were unresponsive to and lacked receptors for this growth factor. In vivo, antisense perlecan-transfected cells generated no tumors, whereas untransfected and vector-transfected cells formed tumors with obvious neovascularization, suggesting that tumor perlecan rather than host perlecan controls tumor growth and angiogenesis. (J Histochem Cytochem 52:1575–1590, 2004)

Key Words: antisense perlecan • heparan sulfate proteoglycan • fibroblast growth factor receptor-2 • tumor growth • tumor angiogenesis

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