The incidence of pancreatic adenocarcinoma has increased in recent decades and the prognosis for patients with this disease remains poor. New information about the pathogenesis of pancreatic cancer that has translational potential would be of great medical and economic importance. Cell culture and animal studies suggest that somatostatin can inhibit pancreatic cancer growth if the tumor cells express somatostatin receptors. Despite these promising results, recent clinical trials of somatostatin analogs as adjuvant treatment of pancreatic cancer have failed because most pancreatic cancer cells do not express somatostatin receptors. This application is centered on the hypothesis that functional somatostatin receptors maintain normal homeostasis within pancreatic cells and loss of these receptors is a critical step in pancreatic carcinogenesis.
Three specific aims will test this hypothesis by carefully defining both the mechanisms of somatostatin receptor loss and function in several experimental models. The first specific aim will, for the first time, carefully demonstrate the lack of expression of specific somatostatin receptor subtypes at both the mRNA and protein level in clinical samples of human pancreatic cancer and preneoplastic lesions. The molecular mechanisms responsible for somatostatin receptor gene silencing will be discovered.
The second aim will correlate the loss of somatostatin receptor expression to tumorigenicity in experimental models of pancreatic carcinogenesis. These experiments will be performed on cultured pancreatic cells and in an animal model. In vitro studies will examine multiple time points during carcinogen exposure for transformation and tumorigenicity while serial sacrifices of exposed animals will capture the progressive development of pancreatic cancer.
The third aim will determine which somatostatin receptor subtypes are important in the inhibition of pancreatic cancer growth. Each somatostatin receptor gene will be individually transfected into a human pancreatic cancer cell line that lacks somatostatin receptors. Effects on growth and responsiveness to somatostatin will be determined using tissue culture and xenografts in nude mice. The molecular mechanisms responsible for the growth inhibitory signal of each receptor subtype in human pancreatic cancer will be determined.
The aims outlined in this application will discover a novel aspect of pancreatic carcinogenesis. Gene therapy to restore the responsiveness of pancreatic cancer to somatostatin analogs by somatostatin receptor gene transfer may become possible from the knowledge gained in these experiments. Since somatostatin expression has been demonstrated in other tumor types, the findings may also be relevant to other cancers.
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