Role of Kupffer cells in the progression of CRC liver metastases after the first stage of ALPPS

• DOI: 10.1038/s41598-018-26082-4
• Publication Date: 2018-05-18T11:32:39Z
• Authors: Rocio García-Pérez; Joana Ferrer Fábrega; Aranzazu Varona-B...; Carlos Manuel Mar...; Beatriz Revilla-Nuin; Laia Cabellos; Romina Pena; Ramón Vilana; Carolina Gonzalez...; Juan Carlos Garcí...; José Fuster Obregón
• Keywords: Male; Kupffer Cells; Portal Vein; Macrophages; Liver Neoplasms; Adenocarcinoma; Article; Rats; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Liver; Disease Progression; Tumor Cells, Cultured; Animals; Hepatectomy; Postoperative Period; Treatment Failure; Colorectal Neoplasms; Ligation

AbstractAssociated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been suggested as a potential therapy for extensive bilobar liver tumors, although in some circumstances this technique may induce tumor progression, a fact still not well studied. Our aim was to study tumor hepatic progression induced by the first step of ALPPS in a WAG/Rij rat syngenic model of metastatic colorectal carcinoma by subcapsular CC531 cell line inoculation. ALPPS induced: tumor progression on deportalized lobe and metastases; expression of hepatic vasculogenic factors (HIF1-α and VEGF); and a dramatic increase of Kupffer cells (KCs) and tumor-associated macrophages (TAMs). Interestingly, KCs expressed COX-2 (M1 polarization), while TAMs expressed mainly arginase-1 (M2 polarization). ALPPS also induced a decrease of tumor-infiltrating lymphocytes and an increase of intrahepatic T lymphocytes. Thus, ALPPS technique seems to induce a hypoxic environment, which enhances hepatic HIF1-α and VEGF expression and may promote KCs and TAMs polarization. Consequently, the regenerative stimulus seems to be driven by a pro-inflammatory and hypoxic environment, in which M1 intrahepatic macrophages expressing COX-2 and T-Lymphocytes play a key role, facts which may be related with the tumor progression observed.