The role of insulin-like growth factor II in the malignant transformation of rat liver oval cells

Abstract

(IGF II), transforming growth factor a, and hepatocyte Oval cells are small nonparenchymal epithelial cells growth factor. that first appear in the periportal areas of the liver and IGF II, a polypeptide of 67 amino acids, is structurally thereafter invade the whole parenchyma when mice or related to proinsulin. 1,2 It can bind specifically and with high rats are exposed to a variety of chemical carcinogens.affinity to two structurally unrelated receptors, the type 1 In the present study we have analyzed the expression and type 2 IGF receptors (IGF1R and M6P/IGF2R, respecof insulin-like growth factor II (IGF II) in the recently tively). 3-8 IGF1R, which resembles the insulin receptor, is established oval cell line OC/CDE 22 and its malignantly a disulfide-linked heterotetrameric (a 2 b 2 ) transmembrame transformed counterpart (the M22 cells) and the biologiglycoprotein with an intracellular tyrosine kinase domain. 9,10 cal consequences of the constitutive expression of IGF M6P/IGF2R (i.e., the cation-independent mannose-6-phos-II in oval cells. OC/CDE 22 cells do not express the abovementioned growth factor, whereas the M22 cells do and phate receptor) is a single-chain polypeptide without tyrosine addition of a neutralizing anti-IGF II antibody to M22 kinase activity but associated with a G-protein signalling cells resulted in an almost complete proliferation stop. pathway involved in lysosomal enzyme targetting. 5,8,11 IGF II The presence of type 1 as well as type 2 insulin-like expression is strictly regulated in a tissue-and developmentgrowth factor receptors in OC/CDE 22 and M22 cells was specific manner, 12,13 and parentally imprinted. 14,15 IGF II is revealed by Northern blotting; however, only neutraliz-present in the fetus, with liver being the main source, but its ing antibodies directed against the type 1 IGF receptor expression is rapidly down-regulated shortly after birth. In were able to inhibit the proliferation of the cultured oval normal adult liver tissue the IGF II concentration is low to cells. Finally, transfection of an IGF II complementary undetectable, but it has been shown to increase significantly DNA (cDNA) into OC/CDE 22 cells resulted in the release in hepatocellular carcinomas and its immediate precursors of active IGF II into the extracellular medium but not in in woodchucks, 16,17 called oval cell compartment in the rat liver constitutes a heterogeneous population: most of the cells are well-differentiated bile duct epithelial cells, while a small number of them Strict control of cell proliferation and migration is crucial may function as bipotent ''stem cells'' with the ability to diffor physiological processes such as organ development, ferentiate into bile duct epithelial cells or into hepatowound repair, and normal cell turnover. Unrestricted prolifcytes. 32,33 In normal liver this stem cell compartment is doreration is one of the hallmarks of fully transformed cells and mant and only becomes activated after a massive destruction a prerequisite for the destructive growth p...

The role of wild-type and mutated N-ras in the malignant transformation of liver cells

“…These ®ndings are perfectly in line with a previous report by Serrano et al [31], who showed that the expression of oncogenic ras in primary human cells results in a permanent G1 arrest, this arrest being phenotypically indistinguishable from cellular senescence. For the aim of this study the rat liver epithelial cell line OC/CDE 22 was chosen, since it had successfully been used in the past to analyze the involvement of p53 [32], insulin-like growth factor II [33], and Ha-ras [32,34] in the malignant transformation of liver cells.…”

Reactivation of the maternally imprinted IGF2 allele in TGFα induced hepatocellular carcinomas in mice

“…The mitogenic action of IGF2 is generally thought to function through cross reaction with IGFI receptors and IGFI receptors are not detectable in liver (Rotwein and Hall, 1990). However, IGFI receptors have been detected in malignantly transformed liver cells which overexpress IGF2 (Zhang et al, 1997). The liver is also a rich source of insulin receptors and the insulin signaling molecule, Insulin Receptor Substrate-1, (IRS-1) (Furusaka et al, 1994;Tanaka and Wands, 1996a,b;Nishiyama and Wands, 1992).…”

Obesity-related hepatocellular carcinoma: roles of risk factors altered in obesity

“…IGF-II has been shown to induce proliferation of malignantly transformed liver oval cells (M22 cells) via an autocrine mechanism when binding to IGF-IR in vitro; however, transfection of an IGF-II complementary DNA into normal oval cells (OC/CDE 22 cells) does not cause a malignant transformation. (173) This finding suggests that IGF-II may only exert mitogenic effect on malignant liver oval cells themselves. Additionally, proliferation and differentiation of liver oval cells can be negatively regulated by IGFBP-3 via TGF-beta pathway both in vivo and in vitro, suggesting that decreased IGFBP-3 may potentiate aberrant proliferation of oval cells.…”