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Pancreatic Adenocarcinoma Signaling

Pancreatic adenocarcinoma, the malignant neoplasm of exocrine duct cells, evolves from a progressive cascade of cellular, morphological and architectural changes from normal ductal epithelium through pre-neoplastic lesions termed pancreatic intraepithelial neoplasia (PanIN). Pancreatic cancers overexpress RTKs, EGFR and TGF-βRs. The expression of RTKs and their growth factor ligands is an early event in the development of pancreatic cancer (PanIN-1A and PanIN-1B stages). The activation of RTKs triggers a signaling cascade which involves GRB2 and ERK/MAPK activation, ultimately resulting in a cellular proliferative response. As pancreatic cancers progress, KRas is activated by RTK-induced GEFs, which in turn activates the Raf-MEK1/2-ERK-Elk1 pathway resulting in cell proliferation and anti-apoptotic events...

Pancreatic Adenocarcinoma Signaling

Pathway Summary

Pancreatic adenocarcinoma, the malignant neoplasm of exocrine duct cells, evolves from a progressive cascade of cellular, morphological and architectural changes from normal ductal epithelium through pre-neoplastic lesions termed pancreatic intraepithelial neoplasia (PanIN). Pancreatic cancers overexpress RTKs, EGFR and TGF-βRs. The expression of RTKs and their growth factor ligands is an early event in the development of pancreatic cancer (PanIN-1A and PanIN-1B stages). The activation of RTKs triggers a signaling cascade which involves GRB2 and ERK/MAPK activation, ultimately resulting in a cellular proliferative response. As pancreatic cancers progress, KRas is activated by RTK-induced GEFs, which in turn activates the Raf-MEK1/2-ERK-Elk1 pathway resulting in cell proliferation and anti-apoptotic events. In addition, the GEF-induced activation of Rho family GTPases (Rho, Rac and Cdc42) activate their downstream effectors MEK1/2 and PI3K, which further enhance ERK/Elk1 and AKT/NF-κB mediated transcription. NF-κB controls VEGF, MMP, Bcl2, BclXL, Cyclin D1, COX2 and Survivin gene transcription to regulate tumor growth, tissue invasion and apoptosis inhibition.During PanIN-2 and PanIN-3 stages, aberrant expression of EGFR enhances tumor growth, invasion and motility. After ligand binding, EGFR dimerizes and is phosphorylated, resulting in the activation of the Notch1 pathway and increased cellular proliferation. For signal propagation, the cytoplasmic domains of EGFR/Her2 receptor are also associated with JAKs. Activation of JAKs occurs upon ligand-mediated receptor multimerization allowing trans-phosphorylation. Activated JAKs subsequently phosphorylate STATs which control the G0-G1 phase transition.Further manifestations of pancreatic tissue pseudostratifications and progression to pancreatic adenocarcinoma occur as a result of inactivation of TGF-β/TGF-βRs, p53, SMAD4 and BRCA2 genes. The growth inhibitory effects of TGF-β are mediated through the induction of CKIs such as p15(INK4B), p21(CIP1), p27(KIP1) and down-regulation of CDKs and cyclins such as Cyclin D, Cyclin E, CDK2 and CDK4. These proteins are critical for regulation of cell cycle progression and maintenance of gatekeeper protein Rb in a hypo-phosphorylated state. SMAD4 tumor suppressor gene along with SMAD2/3 and E2Fs play a critical role in signal transduction through the TGF-β receptors. They act through p15(INK4B) to inhibit CDK4 interaction with Cyclin D1. The Cyclin D1-CDK4 complex phosphorylates Rb, which frees E2F to act as a transcription factor with the resultant progression of the cell cycle to S phase.Another putative tumor suppressor gene, p14(ARF), binds to the MDM2 protein and inhibits its interaction with DNA damage induced-p53. p53 gene mutations are common in pancreatic adenocarcinoma and serve a critical role at the G1-S phase transition by allowing entry into S phase in response to DNA damage. The p53 gene exerts an inhibitory effect on CDK4 directly and indirectly through p21(CIP1). Wild-type p53 is also necessary for the efficient activation of apoptosis in response to DNA damage, a mechanism counteracted by BRCA2. Germline BRCA2 gene mutations lead to sporadic pancreatic carcinomas. Efforts to prevent pancreatic cancer must emphasize a cessation of alcohol and smoking,as there are higher rates of pancreatic cancer in patients with a history of drinking and smoking. An additional measure which may be effective in preventing pancreatic cancer is via weight management, as pancreatic cancer occurs at a higher rate in the obese population.

Pancreatic Adenocarcinoma Signaling Genes list

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