During the last grant period, we have obtained evidence that the expression of connective tissue growth factor (CTGF) is elevated in human pancreatic tumors, but not in normal pancreas or pancreatitis. Since pancreatic tumors are highly hypoxia and CTGF is known to be hypoxia inducible, we have focused this grant to understand the role of hypoxia and CTGF in pancreatic tumor progression. The basis for these studies to investigate the importance of CTGF in pancreatic tumor progression derive from our demonstration that targeted inhibition of CTGF with a monoclonal specific antibody results in significant growth inhibition of two different pancreatic cancer cell lines implanted as subcutaneous tumors. In this grant, we will focus on determining the mechanistic role of CTGF and its individual domains on pancreatic tumor progression under normoxic and hypoxic conditions. Our preliminary data suggests that CTGF is able to enhance the growth of pancreatic tumor cells. Induction of CTGF had no effect on cell growth on plastic, but significantly enhanced spheroid growth in soft agar. Most striking was the increase in cell adhesion induced by CTGF expression. These changes in cell adhesion that are necessary for 3-D growth lead us to test the hypothesis that one of the major roles of CTGF in malignant progression is to 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 under normoxic and hypoxic conditions using domain specific deletion mutants in cells that are manipulated to express different levels of HIF-1, 2) determine how important CTGF is for 3-D growth and invasion under normoxic and hypoxic conditions, 3) determine how inhibition of CTGF mediated adhesion affects metastatic growth, 4) determine how inhibition of cell adhesion by CTGF affects subcutaneous and orthotopic tumor growth of pancreatic tumor cells, 5) determine the role of stromal and tumor cell CTGF on tumor growth, 6) determine how effective the combination of CTGF Ab and ionizing radiation or gemcitabine are in controlling pancreatic tumor growth compared to ionizing radiation or gemcitabine alone. In summary, the proposed studies are intended to address an important mechanism by which CTGF affects tumor progression in pancreatic cancers and to determine how effective it is in combination therapy to bring it to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116685-04
Application #
7666292
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Jhappan, Chamelli
Project Start
2006-09-27
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$241,835
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
LaGory, Edward L; Wu, Colleen; Taniguchi, Cullen M et al. (2015) Suppression of PGC-1? Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma. Cell Rep 12:116-127
Finger, Elizabeth C; Castellini, Laura; Rankin, Erinn B et al. (2015) Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells. Proc Natl Acad Sci U S A 112:4441-6
Finger, E C; Cheng, C-F; Williams, T R et al. (2014) CTGF is a therapeutic target for metastatic melanoma. Oncogene 33:1093-100
Rankin, Erinn B; Wu, Colleen; Khatri, Richa et al. (2012) The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 149:63-74
Finger, Elizabeth C; Giaccia, Amato J (2010) Hypoxia, inflammation, and the tumor microenvironment in metastatic disease. Cancer Metastasis Rev 29:285-93
Rankin, Erinn B; Fuh, Katherine C; Taylor, Tiffany E et al. (2010) AXL is an essential factor and therapeutic target for metastatic ovarian cancer. Cancer Res 70:7570-9
Bennewith, Kevin L; Huang, Xin; Ham, Christine M et al. (2009) The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Res 69:775-84
Chan, Denise A; Kawahara, Tiara L A; Sutphin, Patrick D et al. (2009) Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell 15:527-38
Chan, Denise A; Krieg, Adam J; Turcotte, Sandra et al. (2007) HIF gene expression in cancer therapy. Methods Enzymol 435:323-45
Chan, Denise A; Giaccia, Amato J (2007) Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev 26:333-9