Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis
Yanyu Zhang, Jessica Cedervall, Anahita Hamidi, Melanie Herre, Kati Viitaniemi, Gabriela D’Amico, Zuoxiu Miao, Ragaseema Valsala Madhavan Unnithan, Alessandra Vaccaro, Luuk van Hooren, Maria Georganaki, Åsa Thulin, Qi Qiao, Johanna Andræ, Agneta Siegbahn, Carl‐Henrik Heldin, Kari Alitalo, Christer Betsholtz, Anna Dimberg, Anna‐Karin Olsson
Abstract
Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor β-positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. Here, we show that tumor vascular function, as well as pericyte coverage is significantly impaired in mice with conditional knockout of PDGFB in platelets. A lack of PDGFB in platelets led to enhanced hypoxia and epithelial-to-mesenchymal transition in the primary tumors, elevated levels of circulating tumor cells, and increased spontaneous metastasis to the liver or lungs in two mouse models. These findings establish a previously unknown role for platelet-derived PDGFB, whereby it promotes and maintains vascular integrity in the tumor microenvironment by contributing to the recruitment of pericytes. SIGNIFICANCE: Conditional knockout of PDGFB in platelets demonstrates its previously unknown role in the maintenance of tumor vascular integrity and host protection against metastasis.