During the last grant period, we have obtained evidence that the expression of connective tissue growthfactor (CTGF) is elevated in human pancreatic tumors, but not in normal pancreas or pancreatitis. Sincepancreatic tumors are highly hypoxia and CTGF is known to be hypoxia inducible, we have focused thisgrant to understand the role of hypoxia and CTGF in pancreatic tumor progression. The basis for thesestudies to investigate the importance of CTGF in pancreatic tumor progression derive from ourdemonstration that targeted inhibition of CTGF with a monoclonal specific antibody results in significantgrowth inhibition of two different pancreatic cancer cell lines implanted as subcutaneous tumors. In thiscompetitive renewal, Project 1 will focus on determining the mechanistic role of CTGF and its individualdomains on pancreatic tumor progression under normoxic and hypoxic conditions. Our preliminary datasuggests that CTGF is able to enhance the growth of pancreatic tumor cells. Induction of CTGF had noeffect on cell growth on plastic, but significantly enhanced spheroid growth in soft agar. Most striking was theincrease in cell adhesion induced by CTGF expression. These changes in cell adhesion that are necessaryfor 3-D growth lead us to test the hypothesis that one of the major roles of CTGF in malignant progression isto regulate cell-cell adhesion, and that inhibiting this activity will impact tumor growth and metastases. Thus,the aims of this proposal are to 1) determine how CTGF affects cell adhesion of pancreatic tumor cells undernormoxic and hypoxic conditions using domain specific deletion mutants in cells that are manipulated toexpress different levels of HIF-1 (Project 3), 2) determine how important CTGF is for 3-D growth andinvasion under normoxic and hypoxic conditions, 3) determine how inhibition of CTGF mediated adhesionaffects metastatic growth, 4) determine how inhibition of cell adhesion by CTGF affects subcutaneous andorthotopic tumor growth of pancreatic tumor cells and in collaboration with Project 4 head and neck tumors,5) determine the role of stromal and tumor cell CTGF on tumor growth, 6) determine how effective thecombination of CTGF Ab and the new hypoxic specific cytotoxin PR-104 are in controlling pancreatic tumorgrowth compared to CTGF Ab and gemcitabine (Project 2). In summary, the proposed studies areintended to address an important mechanism by which CTGF affects tumor progression inpancreatic cancers and to determine how effective it is in combination therapy to bring it to theclinic.
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