Significance of Microenvironment for Prostate Cancer Initiation and Progression

University Of Washington, Seattle WA

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Abstract

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