Platelet C3G protects from liver fibrosis, while enhancing tumor growth through regulation of the immune response

• DOI: 10.1002/path.6403
• Publication Date: 2025-03-10T11:01:17Z
• Authors: Cristina Baquero; Minerva Iniesta‐G...; Nerea Palao; Cristina Fernánde...; Mateo Cueto‐Remacha; Jaime Mancebo; Samuel de la Cáma...; María Rodrigo‐Faus; M Pilar Valdecantos; Angela M Valverde; Celia Sequera; Sara Manzano; Ángel M Cuesta; Alvaro Gutierrez‐...; Paloma Bragado; Carmen Guerrero; Almudena Porras
• Keywords: Liver Cancer; CCL4; Monocyte

Primary liver cancer usually occurs in the context of chronic disease (CLD), association with fibrosis. Platelets have emerged as important regulators CLD and cancer, although their precise function mechanism action need to be clarified. C3G (RapGEF1) regulates platelet activation, adhesion, secretion. Here we evaluate role chemically induced fibrosis associated using genetically modified mouse models. We found that while overexpression full-length platelets decreased by treatment CCl4, overexpressed lacking catalytic domain did not, both cases recruitment was similar. In addition, deletion (PF4-C3GKO model) increased CCl4-induced damage hepatic fibrosis, reducing macrophages. Moreover, early immune response CCl4 altered PF4-C3GKO mice, a remarkable lower activation macrophages monocyte-derived compared WT mice. On other hand, DEN+CCl4, PF4-C3G mice exhibited more larger tumors than accompanied presence platelets, despite having less previous steps. Liver cell populations were also differentially regulated highlighting higher number macrophages, likely pro-inflammatory phenotype, present DEN+CCl4 treatment. Proteins upregulated or downregulated platelet-rich plasma from might regulate tumor development. this regard, enrichment analyses proteomic data showed changes several proteins involved pathways. Additionally, secretion CD40L could contribute antitumor effect. Therefore, presents antifibrotic protumor effects liver, mediated response. © 2025 The Author(s). Journal Pathology published John Wiley & Sons Ltd on behalf Pathological Society Great Britain Ireland.