Differential Impact of Tumor Endothelial Angiopoietin-2 and Podoplanin in Lymphatic Endothelial Cells on HCC Outcomes with Tyrosine Kinase Inhibitor Treatment According to Sex
Simone Lasagni,
Rosina Maria Critelli,
Fabiola Milosa,
Dario Saltini,
Filippo Schepis,
Adriana Romanzi,
Francesco Dituri,
Grazia Serino,
Lorenza Di Marco,
Alessandra Pivetti,
Filippo Scianò,
Gianluigi Giannelli,
Erica Villa
Affiliations
Simone Lasagni
Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy
Rosina Maria Critelli
Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy
Fabiola Milosa
Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy
Dario Saltini
Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy
Filippo Schepis
Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy
Adriana Romanzi
Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy
Francesco Dituri
National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy
Grazia Serino
National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy
Lorenza Di Marco
Clinical and Experimental Medicine Program, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Alessandra Pivetti
Gastroenterology Unit, Azienda Ospedaliero-Universitaria di Modena, 41124 Modena, Italy
Filippo Scianò
Gastroenterology Unit, Azienda Ospedaliero-Universitaria di Modena, 41124 Modena, Italy
Gianluigi Giannelli
National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy
Erica Villa
Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy
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.
