Alpha v Beta 6 Integrin is a Specific Immunohistological Marker in the Diagnosis of Cholangiocarcinoma

Background and Aims: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the most common primary hepatic malignancies. Immunohistological differentiation of both tumors is pivotal for treatment and prognosis. Recently, alpha V beta 6 integrin (avb6) was found strongly upregulated in experimental biliary fibrosis and in patients with cholestatic liver disease, but its expression in primary liver cells and diagnostic applicability to distinguish primary cancers is unknown. Methods: 77 HCC and 73 CC paraffin-embedded tissues from patients who underwent partial hepatectomy were collected and immunostained for avb6 and the transcription factor Snail. Avb6 mRNA expression was quantified from CC and HCC tissues, and normal liver. Also, gene expression of the beta6 chain was quantified by RT-PCR in human cell lines including cholangiocarcinoma cells (TFK-1), hepatocellular carcinoma cells (HepG2), immortalized cholangiocytes (MMNK-1) and primary liver cells.

Results: Immunohistological staining for the beta6 receptor was strongly positive on proliferating biliary epithelia in 86% of CC specimens, whereas all HCC were negative. Tumor section positive for beta6 also stained positive for Snail. Beta6 mRNA expression was upregulated in CC tissues and about 100-fold higher compared to HCC and normal liver tissues. In vitro, an extremely high expression of the beta6 chain was detected in TFK-1 cells (73-fold), while expression in MMNK-1 cells was low, and absent in HepG2cells. No association with tumor grade, tumor location, pattern of tumor, fibrosis and mucin expression was found.

Conclusions: Avb6 is dramtically upregulated in CC and associates with expression of Snail indicating epithelial-to-mesenchymal transition. Avb6 can be considered a highly specific immunohistological marker for differentiating primary liver tumors.

Cholangiokarzinom - Epithelial-Mesenchymale Transition - Integrin - Tumormarker