Apoptosis Signaling Pathways in Pancreatic Cancer Pathogenesis
Conventional and investigational cancer therapies have had little to no effect on the course of pancreatic cancer disease progression. Induction of apoptosis plays a major role in the anti-tumoral effects of conventional chemo and radiotherapy, leading to
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Drug Resistance in Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
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Role of Apoptosis in the Outcome of Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
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Molecular Control of Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
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Expression of Canonical Apoptosis Regulators in Pancreatic Cancer . . . . . . . . . . . . . 373
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Effects of the Major Genetic Alterations Observed in Pancreatic Cancer on Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
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Role of NFkB Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
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Role of EMT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
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Tumor-Stromal Interactions and Drug Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
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Role of Wnt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
10 Role of Sonic Hedgehog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 11 Role of Notch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 12 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
J. P. Neoptolemos, R. Urrutia, J. L. Abbruzzese, M. W. Bu¨chler (eds.), Pancreatic Cancer, DOI 10.1007/978-0-387-77498-5_14, # Springer Science+Business Media, LLC 2010
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Apoptosis Signaling Pathways in Pancreatic Cancer Pathogenesis
Abstract: Conventional and investigational cancer therapies have had little to no effect on the course of pancreatic cancer disease progression. Induction of apoptosis plays a major role in the anti-tumoral effects of conventional chemo and radiotherapy, leading to the conclusion that apoptotic pathways must be more dysfunctional in pancreatic cancer than they are in other solid malignancies. However, in vitro and preclinical in vivo studies indicate that human pancreatic cancer cell lines display remarkable heterogeneity in their sensitivities to conventional and investigational therapeutic agents, and some of the ‘‘rules’’ governing sensitivity and resistance are being identified. More importantly, pancreatic cancer is characterized by the presence of a large inflammatory stromal component, and emerging evidence indicates that tumor-stromal interactions further reinforce drug resistance in vivo. Here we will review what is known about the signaling pathways that mediate apoptosis resistance in pan
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