Background: We recently uncovered evidence for a process which appears to be a vital early element of metastasis, namely 'clonal dominance' of primary tumors by metastatically-competent cell variants. Simply put, such cells not only possess the machinery to colonize and grow in distant organ sites, but also have a profound growth advantage over their non-metastatic counterparts within the primary site itself. This process has several far-reaching implications for tumor biology and clinical oncology not the least of which that it may be necessary for the formation of distant metastases. The progression of primary human malignant melanomas from the radial growth phase (RGP) or 'thin' vertical growth phase (VGP) stages to the thicker VGP stage provides a compelling example of the metastatic cell 'clonal dominance' model. The major long-term objective of this project is to determine some of the possible ways by which normal cells of the local environment of primary melanomas may contribute to the 'growth dominant' nature of metastatically-competent human melanoma cells. Recent Pertinent Findings: Coculture of normal human dermal fibroblasts with human melanoma cells can modulate the growth of the latter in a way that is reproducibly a function of tumor progression: RGP or early VGP (metastatically-incompetent) cells are growth inhibited whereas melanoma cells obtained from advanced VGP primary tumors or distant metastases are growth stimulated. Moreover, these results can be duplicated by using conditioned media from normal human dermal fibroblasts, thus implicating the involvement of secreted growth factors. Preliminary experiments indicate the inhibitor is a protein of molecular mass between 28 and 48 Kda, and that transferrin (Tf) or Tf-like molecule is involved in the fibroblast-mediated stimulation of metastatic melanoma cells. Overall Guiding Hypotheses and Significance: It is hypothesized that clonal dominance of metastatic cells in primary human melanomas is in part mediated by the combined effects of paracrine growth factor inhibitors and stimulators liberated by fibroblasts. The growth inhibitor is postulated to be effective on early-stage (non-metastatic) melanoma cells but impotent on more advanced stage (metastatically- competent) subpopulations-- whereas the reverse is postulated for the stimulatory growth factor activity. Distant metastatic growth may also be facilitated by the presence of fibroblasts acting as a 'cellular fertilizer' to help create a more congenial environment for tumor growth.
Specific Aims : Include the following: (i) multistep protein purification and molecular cloning procedures will be undertaken to identify the nature of the inhibitor (called human dermal fibroblast-derived growth inhibitor or 'hDFGI'), clones its cognate CDNA, and study its function on melanoma cell growth and behavior in vitro; (ii) the contribution of Tf as a possible co-factor in fibroblasts-mediated growth stimulation of metastatically-competent melanoma cells will be determined; (iii) the specificity and heterogeneity of the fibroblast-melanoma growth interaction will be evaluated; (iv) the contribution of the inhibitory and stimulatory growth factor activities to human melanoma growth and progression in vivo will be investigated.
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