Published online before print December 30, 2009

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(American Journal of Pathology. 2010;176:981-994.)
© 2010 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2010.080998

Platelet-Derived Growth Factor-B Normalizes Micromorphology and Vessel Function in Vascular Endothelial Growth Factor-A-Induced Squamous Cell Carcinomas

Wiltrud Lederle^*, Nina Linde^*, Julia Heusel^*, Jessica Bzyl, Eva C. Woenne, Stefan Zwick, Mihaela Skobe^¶, Fabian Kiessling, Norbert E. Fusenig^|| and Margareta M. Mueller^*

From the Tumor and Microenvironment Group (A101),^* the Department of Medical Physics in Radiology, and the Division of Differentiation and Carcinogenesis (A080),|| German Cancer Research Center Heidelberg, Germany; the Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany; the Department of Diagnostic Radiology, Medical Physics, University Hospital, Albert Ludwigs University, Freiburg, Germany; and the Mount Sinai School of Medicine,^¶ New York, New York

Vascular endothelial growth factor (VEGF), which is a key regulator of angiogenesis, often induces formation of immature vessels with increased permeability and reduced vessel functionality. Here, we demonstrate that de novo expression of murine (m)VEGF-164 induces malignant and invasive tumor growth of HaCaT keratinocytes. However, the mVEGF-164-induced tumors are ulcerated with a disorganized epithelium that is interrupted by lacunae with limited basement membrane and endothelial cell coverage. Vessel maturation is strongly impaired. Tumor and vessel micromorphology are markedly improved by the combined expression of human platelet-derived growth factor (hPDGF)-B and mVEGF-164. Although tumor size and malignancy are comparable with either mVEGF-164 alone or combined human PDGF-B and mVEGF-164 expression, combined hPDGF-B and mVEGF-164 expression leads to a more solid and compact tumor tissue with a mature functional tumor vasculature and a higher microvessel density, as demonstrated histologically and by dynamic contrast-enhanced magnetic resonance imaging. Treatment of the hPDGF-B- and mVEGF-164-expressing tumors with imatinib mesylate to block PDGF-B signaling reverses this effect. In addition, tumor cell invasion of mVEGF-164 transfectants and mVEGF-164 plus hPDGF-B transfectants in vivo is associated with a marked induction of tumor-derived matrix metalloproteinase-1 and stromal matrix metalloproteinase-9 and -13, as was confirmed in three-dimensional organotypic co-cultures with fibroblasts in vitro. These data clearly demonstrate the need for a concerted action of different growth factors in the establishment of solid tumors with functional vasculature and emphasize the need for a multifactorial therapy.