Angiopoietin-2 regulates vessels encapsulated by tumor clusters positive hepatocellular carcinoma nest-type metastasis via integrin α5β1].

X F Dong, J T Zhong, T Q Liu, Y Y Chen, Y T Tang, J R Yang

Zhonghua yi xue za zhi 2021 Mar 09

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Objective: To investigate the molecular mechanism of nest metastasis in blood vessels encapsulated by tumor clusters (VETC) positive hepatocellular carcinoma (HCC). Methods: A total of 72 paraffin embedded HCC tissue samples were collected. Immunohistochemistry staining with CD34 (vascular endothelial cell marker protein) was used to observe the morphological manifestations of VETC cancer nests in primary tumors, bile duct cancerous thrombi and portal vein cancerous thrombi, and to study the characteristics of hematogenous metastasis of VETC cancer nests. Bioinformatics was used to predict the key proteins closely related to VETC cancer nest formation. Immunohistochemistry was used to detect the expression of angiogenin-2 (Ang-2), integrin α5, Integrin β1, and cyclooxygenase-2 (COX-2) proteins in HCC. Transwell cell migration assay was used to detect the effect of Ang-2/integrin α5β1 protein on the migration ability of endothelial cells and HCC cells. Western blotting was used to detect the effect of Ang-2/integrin α5β1 protein on the activity of focal adhesion kinase (FAK) protein. Results: Of the collected HCC specimens, 27 cases (27/72) were VETC (+), including 3 cases with biliary duct cancerous thrombus, 5 cases with portal vein cancerous thrombus, and 3 cases with both biliary duct cancerous thrombus and portal vein cancerous thrombus. VETC (+) HCC could metastasize to portal vein, bile duct, and liver in the form of cancer nest, and the nests retain their intact structure. Ang-2, integrin α5 and integrin β1 were overexpressed in tumor cells and endothelial cells of VETC (+) HCC nests, while COX-2 was only overexpressed in tumor cells of VETC (+) HCC nest. Ang-2 could promote the migration of HCC cell [(121±12) vs (186±11), P<0.01] and endothelial cells [(81±7) vs (163±14), P<0.01]. Integrin α5β1 activation antagonist ATN-161 could significantly block the ability of Ang-2 to promote the migration of HCC cells [(185±10) vs (135±9), P<0.05] and endothelial cells [(156±14) vs (103±6), P<0.05]. ATN-161 could significantly block the phosphorylation of FAK in HCC and endothelial cells induced by Ang-2. Conclusions: VETC (+) HCC could metastasize as a whole in a nested form, and possesses a specific regulatory protein. Ang-2/α5β1/FAK might be potential protein targets in the treatment of VETC (+) HCC nest-type metastasis.

Citation

X F Dong, J T Zhong, T Q Liu, Y Y Chen, Y T Tang, J R Yang. Angiopoietin-2 regulates vessels encapsulated by tumor clusters positive hepatocellular carcinoma nest-type metastasis via integrin α5β1]. Zhonghua yi xue za zhi. 2021 Mar 09;101(9):654-660