Human pancreatic cancers overexpress several major angiogenic molecules including basic fibroblast growth factor, epidermal growth factor receptor, endothelial nitric oxide synthase, insulin-like growth factor receptor, and vascular endothelial growth factor, and this overexpression is concomitant with elevated transcription factor Sp1 expression and activation. Because these molecules are potentially transactivated by Sp1, disregulated expression and activation of Sp1 may be responsible for aberrant expression of multiple angiogenic molecules, leading, in turn, to the onset of the angiogenic phenotype and sustained tumor growth and metastasis. Therefore, Sp1 may be a critical marker for pancreatic cancer diagnosis and prognosis as well as a novel therapeutic target. This project will test this hypothesis by: 1) defining the prognostic value of Sp1 activation in human pancreatic cancer development and progression. Blood vessel density, expression of angiogenic molecules, and Sp1 expression and activity will be evaluated by examining tissues from normal pancreas and from different PanlN stages of pancreatic adenocarcinoma and pancreatic adenocarcinoma metastases. The relationship between the Sp1 activity, angiogenic phenotype, and various clinicopathologic characteristics of pancreatic cancer will be analyzed. The angiogenic phenotype is predicted to correlate with elevated Sp1 activity and with overexpression of angiogenic molecules, both of which have direct impacts on cancer development and progression. 2) providing evidence of a causal relationship between Sp1 overexpression and the angiogenic phenotype. The angiogenic, tumorigenic, and metastatic potential of various human pancreatic cancer cell lines differing in Sp1 expression will be systematically compared and Sp1 expression in highly and poorly angiogenic human pancreatic epithelial cell lines will be genetically modified to determine the effectsof altered Sp1 activity on the expression of angiogenic molecules, angiogenesis, growth, and metastasis of pancreatic cancer in well-established orthotopic animal models. The level of Sp1 activity is expected to correlate directly with the tumorigenic and metastatic potential of human pancreatic cancer, and the alteration of Sp1 activity is expected to directly change the angiogenic phenotype of tumor cells in vitro and in vivo. 3) exploring the therapeutic effect of targeting Sp1. This exploration will involve two distinct approaches, including a newly generated adenoviral delivery system of the dominant negative Sp1 gone and small molecule inhibitors of Sp1 binding activity. The Sp1 activity, expression of angiogenic molecules, and tumor vessel formation, growth, and metastasis will then be determined with preclinical models. Decreased Sp1 activity is anticipated to inhibit multiple angiogenic molecule expression, decrease angiogenesis, hence suppression of tumor growth and metastasis. Therefore, completion of these studies using molecular and cell biology techniques, animal models, and human specimens will provide insightful information for the development of potential diagnostic and therapeutic strategies for pancreatic cancer.
NIH ExPorter
NIH ExPorter