|The rapid and uncontrolled growth which characterizes the pancreatic cancer cell cycle depends upon many factors, above all, alterations in key genes involved in controlling the cell cycle . More than 90% of pancreatic tumors bear codon 12 K-ras point mutations. This frequency, the highest to be reported for any tumor type which has been described in the early phases of pancreatic carcinogenesis, determines the synthesis of an altered p21 protein [3, 4]. Normal p21 shifts from an active state (bound to GTP) to an inactive state (bound to GDP) via its intrinsic GTPase activity, and via its sensitivity to the activity of GAP (GTPase activating protein). The transformed p21 becomes insensitive to GAP thus leading this protein to a constitutive and permanent activation, which stimulates cell growth. Another gene frequently found to be altered in pancreatic cancer is p16 (homozygously deleted in about 40% of pancreatic carcinomas). It is an inhibitor of cyclin-dependent kinase (CDK) 4, which promotes progression of the cell division cycle through late G1 phase to G1/S . Accelerated pancreatic cancer cell growth is, however, not only due to mutations of K-ras, p16 or other genes involved in regulating the cell cycle, but also to an imbalance between stimulatory and inhibitory factors, mainly cytokines. Among the cytokines providing positive signals for pancreatic cancer cell growth, are EGF, IGF I, TGFalpha, interleukin 1alpha [5-13], which originate in peri-tumoral inflammatory cells, but may also be produced by the pancreatic cancer itself thus exerting an autocrine action [9, 14, 15]. To act, all these mediators must first bind to their transmembrane receptors, the majority of which have an intrinsic tyrosine kinase activity which subsequently has a series of intracellular targets. Among these cytokines are the family of mitogen-activated protein kinases (MAPKs) and the extracellular regulated kinases (ERKs) [13, 16, 17].
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