This proposal centers on the mechanisms of the functional communications between a major family of cell surface adhesion receptors, the integrins, and a subset of its ligands, the bone matrix proteins, with an emphasis on osteonectin (SPARC) and a major family of angiogenic growth factors, the VEGFs and its receptors. The context in which these relationships will be examined is prostate cancer. The central hypothesis to be tested in this proposal is that the process of integrin activation preferentially enhances recognition of bone matrix ligands, thereby selectively increasing the metastasis of prostate cancer cells to bone. One of the mechanisms of regulation of integrin activation is via VEGFdependent autocrine loop. The corollary to this hypothesis that the bone matrix ligands alter the VEGF/VEGFR2 expression and further amplify proposed VEGF autocrine loop will also be tested.
Our Specific Aims are:
Aim I. How does integrin activation influence recognition of the bone matrix? We will introduce wild-type and mutant forms of integrin into prostate cancer cells which result in a resting, constitutively activated state or a non-activatable receptor and determine how these states influence recognition of bone matrix ligands. The emphasis of our studies will be the bone protein that is responsible for prostate cancer - bone interactions, SPARC (osteonectin). We will then determine the mechanisms of SPARC interactions with integrins on prostate cancer cells that are known to metastasize to bone relative to those with low metastatic potential. We will determine whether activation or neutralization of the V-ALIA pathway alters integrin function and SPARC recognition on these cells.
Aim II. What is the role of newly identified regulatory circuits in the V-ALIA pathway in prostate cancer? We will assess how the bone matrix protein SPARC influences the expression of VEGFs and VEGFRs. We will use purified protein as well as bone extracts from normal and SPARC (-/-) mice.
Aim III. What is the role of the V-ALIA pathway in vivo? We will determine the integrin activation states of human prostate tumors that have metastasized to bone as compared to tumors localized to the prostate. We will compare the growth characteristics in bone environment of cell lines expressing inactive and active integrins. We will compare the tumor growth characteristics within the bones of WT and SPARC (-/-) mice. Our efforts to determine how the recognition of bone specific matrix proteins by prostate tumor cells occurs and what mechanisms regulate this recognition will provide insights into a basic and potentially important process operative in the growth and metastasis of prostate cancer. ? ?
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