Hedgehog Signaling Pathways in Pancreatic Cancer Pathogenesis
Recent research has identified the Hedgehog signaling pathway as a key player in pancreatic cancer. The pathway is normally silent in the adult pancreas, but it gets activated in precursor lesions of pancreatic cancer as well as in invasive and metastatic
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Key Research Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 The Hedgehog Signaling Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 The Hedgehog Signaling Pathway in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Different Modalities of Hedgehog Signaling Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 Pancreatic Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408 Hedgehog Signaling in Pancreatic Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409 Hedgehog Signaling in Tumor Stroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 Hedgehog Signaling and Pancreatic Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412 Hedgehog Signaling in Invasive Tumors and Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Hedgehog Signaling in Other Pancreatic Lesions and Tumors . . . . . . . . . . . . . . . . . . . . . . 413
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Future Scientific Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
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Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
J. P. Neoptolemos, R. Urrutia, J. L. Abbruzzese, M. W. Bu¨chler (eds.), Pancreatic Cancer, DOI 10.1007/978-0-387-77498-5_16, # Springer Science+Business Media, LLC 2010
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Hedgehog Signaling Pathways in Pancreatic Cancer Pathogenesis
Abstract: Recent research has identified the Hedgehog signaling pathway as a key player in pancreatic cancer. The pathway is normally silent in the adult pancreas, but it gets activated in precursor lesions of pancreatic cancer as well as in invasive and metastatic pancreatic adenocarcinoma. Interestingly, mutations in the components of Hedgehog signaling have not been identified in pancreatic cancer; instead, the mechanism of activation relies on overexpression of one of the pathway ligands, Sonic Hedgehog, by the tumor cells. It is under investigation whether the secreted Hedgehog ligand mediates interactions among different cell types within the tumor. Our current knowledge indicates that the Hedgehog signaling pathway gets activated downstream of Kras (which is activated through a mutation in the vast majority of pancreatic cancers) and it synergizes with the Kras activity to promote tumor progression. Interestingly, the activity of the Hedgehog pathway appears to regulate processes such as tumor metastasis, one of the factors that preclude treatment in human patients. Current research is aimed at fully understanding the role of the pathway in pancreas cancer formation and progression and at establishing whether inhibition of
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