Differential Impact of Tumor Endothelial Angiopoietin-2 and Podoplanin in Lymphatic Endothelial Cells on HCC Outcomes with Tyrosine Kinase Inhibitor Treatment According to Sex

Author:

Lasagni Simone12ORCID,Critelli Rosina Maria1,Milosa Fabiola1ORCID,Saltini Dario1ORCID,Schepis Filippo1ORCID,Romanzi Adriana12ORCID,Dituri Francesco3,Serino Grazia3ORCID,Di Marco Lorenza2ORCID,Pivetti Alessandra4,Scianò Filippo4,Giannelli Gianluigi3ORCID,Villa Erica1ORCID

Affiliation:

1. Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy

2. Clinical and Experimental Medicine Program, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy

3. National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy

4. Gastroenterology Unit, Azienda Ospedaliero-Universitaria di Modena, 41124 Modena, Italy

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments are available to a minority of patients, as HCC is often diagnosed at an advanced stage. For patients with unresectable and multifocal HCC, tyrosine kinase inhibitor drugs (TKIs) are the only potential treatment option. Despite extensive research, predictors of response to these therapies remain elusive. This study aimed to analyze the biological and histopathological characteristics of HCC patients treated with TKIs, focusing on angiogenesis and lymphangiogenesis. Immunohistochemistry quantified the expression of angiopoietin-2 (Ang2), lymphatic endothelial cells (LEC) podoplanin, and C-type Lectin Domain Family 2 (CLEC-2), key factors in neoangiogenesis and lymphangiogenesis. An increased expression of endothelial Ang2 and LEC podoplanin predicted a lower risk of metastasis. Female patients had significantly longer overall survival and survival on TKIs, associated with higher tumor expression of endothelial Ang2 and LEC podoplanin. Moreover, LEC podoplanin expression and a longer time on TKIs were independently correlated with improved survival on TKI therapy at Cox regression analysis. These findings suggest that endothelial Ang2 and LEC podoplanin could be potential biomarkers for predicting treatment outcomes and guiding therapeutic strategies in HCC patients treated with TKIs.

Funder

Associazione Italiana sulla Ricerca sul Cancro

AIFA Independent Research

Ministero Salute

Publisher

MDPI AG

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