β4 and β6 Integrin Expression Is Associated with the Subclassification and Clinicopathological Features of Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous group of cancers of the intrahepatic biliary tract. However, few studies have evaluated integrin expression according to an ICC subgroup. We immunohistochemically investigated α6β4 (β4) and αvβ6 (β6) integrin expressions in 48 ICCs, and evaluated their relationship with clinical and pathological parameters and ligand expression, as well as transforming growth factor (TGF)-β1. β4 and β6 expressions were detected in 46 (96%) and 35 (73%) ICC cases, respectively. We classified ICC into negative, low (β4, 29 cases; β6, 36 cases), or high (β4, 19 cases; β6, 12 cases) integrin expression groups. β4 and β6 integrin levels were higher in the non-peripheral central localization type ICC than in the peripheral localization type; they were also higher in the periductal-infiltrating or intraductal-growth types than in the mass-forming type ICC; lastly, they were higher in the well-differentiated type than in the poorly-differentiated type ICC. High expression was related to bile duct invasion. In addition, β4 and β6 expressions were associated with mucin production and the expression of cytoplasmic epithelial membrane antigen, laminin-5, and tenascin-C. TGF-β1 was correlated with β6 expression and poor overall survival. These results suggest that integrin expression is associated with subclassification and clinicopathological features of ICC through the coincident expression of their ligands and TGF-β1.

Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells

“…Expression was highly specific to CCA cells compared to adjacent non-malignant biliary epithelia that had an undetectable level of integrin αvβ6. These results are consistent with those observed in CCA tissues from other ethnic groups, including Swiss ( 26 ), Japanese ( 21 ), and Chinese populations ( 22 ). Notably, the survival time of CCA patients who had low/negative integrin αvβ6 protein expression was significantly longer than the survival time of those who had high integrin αvβ6 expression ( Figures 1D,E ).…”

“…Binding between the target antigen on cancerous cells and the extracellular antigen-binding domain of the CAR molecule leads to activation of CAR T cells to kill cancerous cells. An attractive potential target antigen in solid tumors is integrin αvβ6 because it is overexpressed in multiple epithelial malignancies, including pancreatic ductal adenocarcinoma ( 16 ), ovarian cancer ( 17 ), head and neck squamous cell carcinoma ( 18 , 19 ), breast cancer ( 20 ), and CCA ( 21 , 22 ). Integrin αvβ6 is also a target for diagnostic imaging and anti-cancer therapies ( 19 ).…”

<p>NRP1 is a Prognostic Factor and Promotes the Growth and Migration of Cells in Intrahepatic Cholangiocarcinoma</p>

“…6 Therefore, identification of novel therapeutic molecular targets is essential for improving the prognosis of ICC. 7,8 NRP1 was first discovered as an adhesion molecule in the frog nervous system in 1987. 9 It is a non-tyrosine kinase transmembrane glycoprotein located on the cell surface and plays a role of a co-receptor for secreted Semaphorin-3A (Sema3A).…”

Translating Biomarkers of Cholangiocarcinoma for Theranosis: A Systematic Review

“…Similar to CLDN18, Tenascin C (TNC) was also reported in two Japanese studies. However, all 109 tissue samples were from iCCA patients [ 50 , 51 ]. Neither of these studies described TNC in normal liver tissue.…”