Integrins as differential cell lineage markers of primary liver tumors

Abstract

This study analyzed new cell lineage markers for the differential diagnosis between hepatocellular carcinoma (HCC) and cholangiocarcinoma (ChC), as well as the potential pathways of cell-cell and cell-extracellular matrix interactions of neoplastic liver cells during tumor spread and invasion, by comparing the expression of (VLA) integrins, vitronectin receptor, and neural cell adhesion molecule in normal, inflamed, and neoplastic human liver biopsies. All cases of liver cell adenoma and well-differentiated HCC expressed the same set of integrins as observed in normal liver tissue, i.e., VLA-alpha 1 and VLA-beta 1. Poorly differentiated HCC also expressed VLA-alpha 1 and VLA-beta 1, but in addition de-novo expressed VLA-alpha 2, VLA-alpha 3, VLA-alpha 6 and vitronectin receptor. All cases of well-differentiated ChC expressed an identical integrin immunoprofile as observed in normal bile duct epithelium, i.e., VLA-alpha 2, VLA-alpha 3, VLA-alpha 6, VLA-beta 4 and vitronectin receptor, whereas poorly differentiated ChC showed a markedly decreased expression of these integrin subunits. VLA-alpha 1 was constantly absent from all cases of ChC, whereas VLA-beta 4 was never expressed by HCC. Neural cell adhesion molecule, exclusively expressed by proliferating reactive bile ductules in cholestatic and regenerating liver, was constantly absent from both malignant neoplasms. In conclusion, the integrin make up of various liver tumors closely follows that of their normal counterparts. Differences in integrin receptor expression vary according to the cellular origin of the tumors and are associated with a poor differentiation. Our findings suggest that immunohistochemical staining for VLA-alpha 1 and VLA-beta 4 integrin subunits, which highlight the cellular phenotype of the two neoplasms, might be a helpful tool in the differential diagnosis between HCC and ChC.