The Insulinlike Growth Factor And Its Receptor In Pancreatic Diseases

Insulin-like growth factors (IGFs) have been implicated as regulators of cell differentiation and cell proliferation in a number of cell systems and have been reported to play an important role in growth regulation of human tumors.43,44 The IGF family includes IGFs Type I and Type II (IGF-I and IGF-II), which are structurally related to proinsulin. IGF-I is a mitogenic factor that has the ability to bind and activate the insulin receptor as well as the IGF-I receptor.45-48 The IGF-I receptor binds IGF-I with higher affinity than insulin, and in general the mitogenic effects of both factors are mediated by the IGF-I receptor. Ligand binding to the IGF-I receptor results in activation of the intracellular receptor kinase domains and transphosphorylation.45-48 Following receptor phosphory-lation, adapter molecules (IRS-1 and IRS-2) associate with the receptor and are phosphorylated. The presence of a variety of phosphorylation motifs on each of the two IRS proteins enables them to interact with a variety of downstream signaling molecules, which allows them to transmit IGF-I signals as well as to contribute to signal transduction of several cytokine receptors.49-54

In experimental models of AP, the expression of IGF-I and its receptor (IGF-IR) was increased in a temporal fashion. Pancreatic IGF-I levels increased over 50-fold during regeneration, between 1 and 3 days after induction of pancreatitis, reaching a maximum at Day 2. 55,56 IGF-I is localized in fibroblasts within the areas of interstitial tissue and is expressed in primary cultures of pancreatic fibroblasts, but not in cultured pancreatic acinar cells, and IGF-I receptors are expressed in cultured acinar cells.55 This indicates that acinar cell proliferation during regeneration from pancreatitis is mediated at least in part by paracrine release of IGF-I from fibroblasts.

In PC there is an increase in IGF-I receptor expression in comparison with the normal pancreas and also a marked increase in IGF-I.44,57 IGF-I is expressed in the stroma elements in the normal pancreas, but in PC, IGF-I is abundantly expressed in both the cancer cells and in the surrounding stroma in PC tissues.44 Furthermore, the receptor substrates IRS-1 and IRS-2 are also overexpressed in human PC, predominantly in the cancer cells.58,59 Increased IGF-I serum levels were found in 10% of patients with PC, and this was inversely correlated with fasting serum glucose levels, which may indicate that serum IGF-I level is related to altered glucose metabolism.60,61

In vitro experiments in cultured human PC cell lines have revealed that several cell lines express the IGF-I receptor.44 Furthermore, IGF-I stimulates the growth of cultured PC cell lines, and this effect is blocked by a specific anti-IGF-I receptor antibody, suggesting that this mitogenic effect is mediated via the IGF-I receptor.44 In addition, the growth of cultured human PC cells is inhibited by IGF-I receptor antisense oligonu-cleotides that specifically block IGF-I receptor synthesis.44 Together, these observations suggest that the IGF-I receptor mediates mitogenic signaling in PC cells. Furthermore, it has recently been shown that IRS-2 is expressed in cultured PC cells and that IGF-I enhances IRS-2 phosphorylation and PI3-kinase activation in PC cells, suggesting that IRS-2 is an important mediator of mitogenic signaling in PC cells, and that this effect is mediated at least in part via PI3-kinase.59 It has also been demonstrated that IGF-I enhances phosphorylation of IRS-1 in PC cells.58 The in vitro and in vivo data collectively suggest that IGF-I — acting in a paracrine or autocrine manner via the IGF-I receptor — together with the concomitant overexpression of IGF-I, IGF-I receptor, IRS-1, and IRS-2 may participate in aberrant pathways to enhance PC cell growth in vivo.

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