Adhesion Signaling and Tumor Cell Progression

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

The long range goal of this Project is to understand how alterations in cellular environment, particularly change in the interactions of cells with the extracellular matrix (ECM) and growth factors with their receptors, influencing the progression and metastatic behavior of prostate tumor cells. We probe to investigate the changes in adhesion signaling pathways using a well characterized panel of prostate cell lines, representing different stages of progression along a pathway from poorly tumorigenic to highly tumorigenic and metastatic. We will focus on key components of the integrin signaling pathway: the protein tyrosine kinases. Focal Adhesion Kinase (FAK) and Src; a putative downstream effector of FAK/Src function, paxillin (a focal adhesion protein); downstream effectors of integrin signaling, MAP kinase; and putative integrin regulated genes. We will also investigate the role of growth factor mediated signaling pathways as co-regulators of integrin signaling, focusing on the possible synergistic role of growth factors in modulating adhesion signaling through the integrin pathway. The specific aims are three-fold: 1) Using a panel of prostate cancer cell lines we will compare the repertoire of integrin receptors and determine their functional binding to ECM proteins; characterize the integrin-specific signaling responses in the different cell lines by assessing the activation of FAK, the tyrosine phosphorylation of paxillin, and the activation of MEK/MAP kinase; compare the repertoire of growth factor receptors expressed in these cells, and establish biological parameters of adhesion signaling by comparing the motility and tumorigenicity of individual cell lines. 2) Using the poorly tumorigenic cell line LNCaP as a recipient cell, we will determine whether the exogenous activation of integrin signaling pathways significantly enhances "progression" of cells to a more metastatic cell population. 3) Using the tumorigenic cell lines, C4-2, derived from LNCaP, as well as the unrelated tumorigenic cell lines, PC3, we will determine if inhibitor of the integrin signaling pathway using specific dominant negative )dn) expression constructs, block tumorigenicity and/or metastasis. These experiment seek to verify the importance of the adhesion signaling pathways in the development and progression of prostate cancer.