Growth factors produced by VGP primary and metastatic melanoma cells stimulate not only self in an autocrine circuit, but also fibroblasts and endothelial cells in the stroma. In the first aim, we will test the hypothesis that bFGF, PDGF, and VEGF follow a hierarchical pattern of expression during melanoma development in which bFGF is the dominant stimulation factor followed by PDGF as maintenance and survival factor, whereas VEGF requires activation to become the expansion and invasion factor. Each factor appears to have specific functions that complement the other in driving cells from a RGP- to a VGP-like phenotype. In the second aim, we will test for the positive feedback from the activated fibroblasts and endothelial cells.
We propose that the stromal cells produce mitogens for melanoma cells that the malignant cells cannot synthesize but for which they express functional receptors. Specifically, we hypothesize that activated fibroblasts produce IGF-1 and endothelial cells produce endothelins for stimulation of melanoma cells. We will test our hypotheses with adenoviral vectors for overexpression of growth factors and antisense constructs for inhibition of expression. To account for the complex environment in human skin, we will use a skin reconstruction model for in vitro studies and the human skin/SCID mouse chimera model for in vivo growth. We expect to find intricate and interdependent circuits for growth factor cross-talk involving melanoma cells, fibroblasts, and endothelial cells which are essential for progression from non-tumorigenic RGP melanoma to tumorigenic VGP growth with high potential for metastasis.
Fukunaga-Kalabis, M. Santiago-Walker, A., Herlyn, M.: Matricellular proteins produced by melanocytes and melanomas: In search for functions. Cancer Microenvironment 1: 93-102, 2008. PMID 19308688
Zhang, G., Herlyn, M.: Tumor microenvironment for melanoma cells. In: Melanoma development. Molecular Biology, Genetics, and Clinical Application, ed. by A. Bosserhoff, Springer, WienNew York, pp. 297-308, 2011.