Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression

Journal of Experimental & Clinical Cancer Research

Michael Tachezy¹  Jakob Izbicki¹  Marius Kemper²  Florian Gebauer³  Sergey Nikulin⁴  Andrey Poloznikov⁴  Alexander Tonevitsky⁵  Vladimir Galatenko⁶  Alina Schiecke⁷  Daniel Wicklein⁷  Udo Schumacher⁷  Hanna Maar⁷  Tobias Lange⁷  Kristoffer Riecken⁸  Achim Aigner⁹ 

[1] Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany;Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany;Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany;Department of General, Visceral and Tumor Surgery, University Hospital Cologne, Köln, Germany;Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia;Faculty of Biology and Biotechnology, Higher School of Economics University, Moscow, Russia;Faculty of Mechanics and Mathematics, Lomonosov Moscow State University, Moscow, Russia;Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany;Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany;Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Medical Faculty, University of Leipzig, Leipzig, Germany;

关键词: Pancreatic cancer;    Integrin alpha-V;    Metastatic cascade;    TGF-beta signaling;    EMT;   

DOI  :  10.1186/s13046-021-01946-2

来源: Springer

【 摘 要 】

BackgroundMesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis.MethodsKnockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated.ResultsThe knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients.ConclusionCombined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.

【 授权许可】

CC BY