No abstract

Integrins play a pivotal role in organogenesis, by mediating the interactions between differentiating cells and the extracellular matrix. We analyzed the expression of integrins and their ligands during human liver organogenesis. The expression of ␤1, ␤3, and ␤4 integrins and the distribution of several extracellular matrix proteins were studied by immunoperoxidase in fetal liver samples from 5 to 40 weeks' gestation. Hepatoblasts expressed only the ␤1, ␣1, ␣5, ␣6, and ␣9 integrin chains. Fetal hepatocytes, emerging at the 8th week of gestation, initially retained the same combination of integrins, but presented a progressive decrease in their expression levels. After 15 weeks' gestation, the expression levels of ␤1, ␣1, ␣5, and ␣9 reached levels comparable to those observed in the adult state. ␣6 expression became undetectable after 30 weeks' gestation. As compared to hepatoblasts, intrahepatic biliary epithelial cells, differentiating at the 8th week of gestation in the ductal plate, were characterized by the progressive loss of ␣1, the marked induction of ␣6, and the de novo acquisition of the ␤4, ␣2, and ␣3 integrin chains. The disappearance of integrin receptors for laminin on hepatocytes was associated with the rarefaction of laminin in the perisinusoidal matrix, whereas their induction on biliary epithelial cells was associated with laminin deposition at the point of contact with the ductal plate. In conclusion, integrins likely play an important role in the differentiation of the epithelial and endothelial cell populations of the liver. (HEPATOLOGY 1998;26:839-847.)Integrins are membrane receptors for extracellular matrix proteins, which play an essential role in mediating the structural and functional interactions between cells and the extracellular matrix. 1 Previous studies have shown that markedly different combinations of integrins are expressed by the two populations of epithelial cells present in the adult liver, hepatocytes and biliary epithelial cells. [2][3][4] Like other simple epithelial cells, intrahepatic biliary epithelial cells express a large combination of integrin receptors, including the ␣2␤1, ␣3␤1, ␣5␤1, ␣6␤1, ␣9␤1, ␣V␤1, and ␣6␤4 dimers. 2,5 In striking contrast, the integrin repertoire of hepatocytes is restricted to the ␣1␤1, ␣5␤1, and ␣9␤1 dimers. This combination is highly distinctive. 3 The expression of ␣1␤1 integrin, a receptor for collagens and laminin, 6 is very unusual for an epithelial cell, since this integrin receptor is characteristically expressed by fibroblasts, muscle cells, and endothelial cells. Moreover, the absence of ␣6␤4, a characteristic component of hemidesmosomes, 7,8 is unique among the epithelial cells tested so far.It is likely that the differences in the combinations of integrins expressed, respectively, by hepatocytes and biliary epithelial cells are related to the differences in the constitution of their pericellular environments. Like all other lining epithelial cells, intrahepatic biliary epithelial cells are surrounded by a typical basement membran...

Gastroenteropancreatic (GEP) endocrine tumors are hypervascular tumors able to synthesize and secrete high amounts of VEGF. We aimed to study the regulation of VEGF production in GEP endocrine tumors and to test whether some of the drugs currently used in their treatment, such as so- matostatin analogues and mTOR inhibitors, may interfere with VEGF secretion. We therefore analyzed the effects of the somatostatin analogue octreotide, the mTOR inhibitor rapamycin, the PI3K inhibitor LY294002, the MEK1 inhibitor PD98059 and the p38 inhibitor SB203850 on VEGF secretion, assessed by ELISA and Western blotting, in three murine endocrine cell lines, STC-1, INS-r3 and INS-r9. Octreotide and rapamycin induced a significant decrease in VEGF production by all three cell lines; LY294002 significantly inhibited VEGF production by STC-1 and INS-r3 only. We detected no effect of PD98059 whereas SB203850 significantly inhibited VEGF secretion in INS-r3 and INS-r9 cells only. By Western blotting analysis, we observed decreased intracellular levels of VEGF and HIF-1α under octreotide, rapamycin and LY294002. For rapamycin and LY294002, this effect was likely mediated by the inhibition of the mTOR/HIF-1/VEGF pathway. In addition to its well-known anti-secretory effects, octreotide may also act through the inhibition of the PI3K/Akt pathway, as suggested by the decrease in Akt phosphorylation detected in all three cell lines. In conclusion, our study points out to the complex regulation of VEGF synthesis and secretion in neoplastic GEP endocrine cells and suggests that the inhibition of VEGF production by octreotide and rapamycin may contribute to their therapeutic effects.

Purpose: To identify MRI biomarkers that could be used to follow disease progression and therapeutic efficacy in one individual muscle in patients with myotonic dystrophy type 1 (DM1). Materials and Methods:Lower limb MRI and maximal ankle dorsiflexor strength assessment, using a hand-held dynamometer, were performed in 19 DM1 patients and 6 control subjects. The volume of residual muscle tissue of Tibialis Anterior (TA) muscle was chosen as an index for muscle atrophy, and the T2-relaxation-time of the residual muscle tissue was measured to evaluate edema-like lesions. The fat-to-water ratio was assessed using threepoint Dixon images to quantify fat infiltration in the entire muscle.Results: The intra-observer variability of MRI indices ($5.2% for the residual muscle tissue volume and 2.5% for the fat-to-water ratio) was lower than that of the dorsiflexor torque measurement ($11.5%). A high correlation (r ¼ 0.91) was found between maximal ankle dorsiflexor strength and residual TA muscle tissue volume in DM1 patients. Increases in the fat-to-water ratio and T2-relaxation-time were associated with a decrease in maximal ankle dorsiflexor strength.Conclusion: MRI appears as a noninvasive method which can be used to follow disease progression and therapeutic efficacy.