Microenvironmental Regulation of Tumor Progression

DESCRIPTION (provided by applicant): Transgenic mouse models of human cancers present unique opportunities to elucidate important cellular and genetic pathways of cancer development, through which normal cells progressively are converted into aberrant cancers. The overall goal of this proposal is to identify cellular signaling pathways impacting tumor development regulated by collagenolytic matrix metalloproteinases (MMPs) and their major stromal substrate, type I collagen, during squamous neoplastic progression in the skin. We will address the characteristics and functional significance of epithelial-stromal interactions regulated by collagenolytic MMPs and type I collagen by combined in vivo and in vitro approaches. The specific aims of this proposal are: Aim 1. Determine the mechanism(s) of type I collagen remodeling during tumor progression. We will determine the expression, localization, and activity of collagenolytic enzymes, and expression, synthesis, and degradation characteristics of type I collagen by molecular, biochemical, morphologic, and histochemical criteria during the development and metastasis of epithelial cancer in a transgenic mouse model of squamous carcinoma development. Aim 2. Determine the consequences of altered type I collagen degradation in vivo: Altered substrate susceptibility. We will determine the impact of collagenaseresistant type I collagen on neoplastic progression, tumorigenesis, tumor stroma development, and the local metastasis of cancers in HPV16 transgenic mice. Aim 3. Determine the consequences of type I collagen remodeling on cell behavior. We will determine the functional consequences of type I collagen remodeling on epithelial and endothelial cell behavior by combined in vivo and in vitro analyses. These studies will reveal the molecular and cellular mechanisms engaged by different populations of cells resulting from type I collagen remodeling during multi-stage neoplastic progression. The immediate ramifications of this work are in its applications to use of MMP-Inhibitors (MPIs) as anticancer agents and will provide proof-of-principle that eliminating productive access to a critical MMP substrate is an efficacious intervention for neoplastic progression. Only a thorough understanding of the actions and effects of MMPs and their major substrates will effectively guide use of MPIs in the treatment of cancer.