Platelet-Derived PDGFB Promotes Recruitment of Cancer-Associated Fibroblasts, Deposition of Extracellular Matrix and Tgfβ Signaling in the Tumor Microenvironment.

Abstract

Simple SummaryThe aim of this study was to investigate the relative contribution of PDGFB derived specifically from platelets to the remodeling of the extracellular matrix (ECM) in tumors. Platelets are a major source of growth factors, which are released from the platelet granules upon activation. Platelets are continuously activated in the tumor microenvironment, due to their similarities to a wound. However, the role of platelet-derived factors in ECM remodeling has not been fully addressed. To this end, we made use of a mouse model with conditional deletion of PDGFB in platelets, which was crossbred to the RIP1-Tag2 model for pancreatic neuroendocrine carcinoma. The amount of tumor-associated PDGFB protein showed a 10-fold reduction in mice lacking PDGFB in platelets. Moreover, ECM deposition, the amount of cancer-associated fibroblasts and TGFβ signaling were all reduced in tumors from mice with platelet-specific deletion of PDGFB, demonstrating the significant contribution of a platelet-derived factor to ECM remodeling in tumors.Platelets constitute a major reservoir of platelet-derived growth factor B (PDGFB) and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. To address the specific role of platelet-derived PDGFB in the tumor microenvironment, we have created a mouse model with conditional knockout of PDGFB in platelets (pl-PDGFB KO). Lack of PDGFB in platelets resulted in 10-fold lower PDGFB concentration in the tumor microenvironment, fewer cancer-associated fibroblasts and reduced deposition of the extracellular matrix (ECM) molecules fibronectin and collagen I in the orthotopic RIP1-Tag2 model for pancreatic neuroendocrine cancer. Myosin light chain phosphorylation, promoting cell contraction and, consequently, the mechano-induced release of active transforming growth factor (TGF) β from extracellular compartments, was reduced in tumors from pl-PDGFB KO mice. In agreement, TGFβ signaling, measured as phosphorylated Smad2, was significantly hampered in tumors from mice lacking PDGFB in their platelets, providing a plausible explanation for the reduced deposition of extracellular matrix. These findings indicate a major contribution of platelet-derived PDGFB to a malignant transformation of the tumor microenvironment and address for the first time the role of PDGFB released specifically from platelets in the remodeling of the ECM in tumors.