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Angiogenic balance in human melanoma: Expression of VEGF, bFGF, IL‐8, PDGF and angiostatin in relation to vascular density of xenografts in vivo
Author(s) -
Westphal Johan R.,
Van't Hullenaar Rianne,
Peek Ron,
Willems Riki W.,
Crickard Kent,
Crickard Ulla,
Askaa Jon,
Clemmensen Inge,
Ruiter Dirk J.,
De Waal Robert M. W.
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(20000615)86:6<768::aid-ijc3>3.0.co;2-e
Subject(s) - angiostatin , angiogenesis , biology , cell culture , in vivo , basic fibroblast growth factor , cancer research , neovascularization , endothelial stem cell , in vitro , microbiology and biotechnology , pathology , immunology , growth factor , medicine , biochemistry , genetics , receptor
Tumor angiogenesis, a major requirement for tumor outgrowth and metastasis formation, is regulated by pro‐ and anti‐angiogenic factors. We have studied the expression of a panel of angiogenic factors, and of the angiogenesis inhibitor angiostatin, in a panel of human melanoma cell lines giving rise to xenografts with different vascular densities. Angiogenic‐factor expression was analyzed in vitro (cell lines) and in vivo (xenografts), both at mRNA (RT‐PCR and Northern blot) and at protein level (ELISA and Western blot). In vitro angiostatin generation was assessed by Western‐blot analysis. Expression of bFGF and VEGF was clearly correlated with a high degree of vascularization, confirming the importance of these factors for tumor angiogenesis. In addition, there was exclusive or elevated in vitro expression of angiogenic factors IL‐8, PDGF‐AB, and, to a lesser extent, midkine in cell lines that formed highly vascularized tumors. A similar angiogenic‐factor‐expression pattern was found in the corresponding xenografts, with the exception of VEGF. In most cell lines, this factor had low expression in vitro which was strongly enhanced in vivo. Although all 8 melanoma cell lines were able to excise the angiostatin fragment from the plasminogen parent molecule in vitro, cell lines BLM and M14 showed the most potent angiostatin generation. In vitro angiostatin generation by cell lysates prepared from melanoma xenografts was comparable in all xenograft types. Thus, in our model system we found no correlation between angiostatin generation and vascular density. Our study has limited the number of pro‐angiogenic factors that may be involved in melanoma angiogenesis, and provides evidence for the notion that regulation of tumor angiogenesis is dependent on multiple factors. Inhibition of angiogenesis for therapeutic purposes, therefore, should preferably not concentrate on a single factor. Int. J. Cancer 86:768–776, 2000. © 2000 Wiley‐Liss, Inc.