Significance of Microenvironment for Prostate Cancer Initiation and Progression

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DESCRIPTION (provided by applicant): Recently it has become evident that although it is the prostate epithelial cell that is transformed into prostate adenocarcinoma, the stromal components of the prostate strongly influence the transformation process and ultimate fate of the transformed cell. This program will define the components of the human prostate stromal microenvironment, the contribution of stromal and epithelial cells to this environment and effects of factors associated with induction of prostate cancer e.g. age, oxidative stress, inflammation product, on the stromal components, and mechanisms of action of selected components. Products arising from this program that will be available to the research community will include but are not limited to: functional blocking human monoclonal antibodies to matrix components, microarray and proteomic databases, preclinical models for evaluation of stromal factors on human tissue. This program will consist of three projects that include: 1. The Aged Microenvironment as a Contributor to Carcinogenesis :Aim 1: Identify molecular changes in the major cellular and matrix constituents of stroma that occur in association with aging. Aim 2: Determine the influence of specific age-associated stromal-derived paracrine factors toward tumor growth/ invasion/ differentiation. Aim 3: Determine if deficiencies in DMA repair mechanisms contribute to molecular aging in the tumor microenvironment. Aim 4. Evaluate hypothesis that aging/senescence of prostate stroma increases characteristics of wound/stress response (co-Aim with Plymate Project). 2. Paracrine and Juxtacrine Mediation of Prostate Cancer Progression : Aim 1. Use of tissue recombination to model cancer progression, Aim 2. Identification and characterization of mesenchymal regulators of prostate development. Aim 3. Juxtacrine signaling models involving tumor and senescent fibroblasts. 3. Laminin Dysregulation in Prostate Cancer: Aim1.Define the laminin chains and integrin subunits in normal and malignant prostate tissue. Aim 2. Determine function of laminin changes in prostate cancer. Aim 3. Determine age-induced changes in laminin, signaling and transcription on proteolytic remodeling of ECM with increased invasion of the mesenchyme. The purpose of this proposal is to define the effects of the prostate environment on development and progression of prostate cancer. Also we will determine how inhibition of these microenvironmental factors can be used as potential therapy for prostate cancer prevention and progression.