Abstract
Evidence accumulated in the past decade supports a crucial role for bone marrow derived cells (BMDCs) in the surrounding tumor microenvironment as critical components regulating primary tumor growth and malignant transformation. Multiple types of BMDCs, including macrophages, T-regs, and neutrophils, contribute to immuno-suppression, and pro-angiogenesis within the tumor microenvironment. In our study, we demonstrated a sub-population of myeloid derived suppressor cells (MDSCs) in peripheral blood in both mice model and glioma patients, which express KDR. The number of KDR(+) MDSCs is positively correlated with pathological/histological grades of tumors. The Grade III and GBM patients have more KDR(+) MDSCs than low-grade patients. In the cohort of patients diagnosed as grade II astrocytoma, the patients, who have higher number of KDR(+) MDSCs, have less progression free survival. The functional role of KDR(+) MDSCs has been studied with Rosa26-cre/KDR(fl/fl) mice (KDR-KO). The bone marrow cells from KDR-KO mice were transplanted into RCAS-tva/PDGF-BB mice at early stage (week 2). Knocking out KDR in bone marrow derived cells led to the delay of progression of low-grade tumor, which was driven by PDGF-BB. The median survival of tumor bearing mice was significantly increased. Moreover, we isolated KDR(+) hematopoietic progenitor cells from bone marrow of tumor bearing mice, and identified that the TGF-b signaling and inhibitor of DNA binding protein-2 (ID2) served as upstream mediators for KDR(+) MDSCs during development of gliomas. With ID2 knockout mice, we recapitulated the phenotype of KDR-bone marrow knockout in tumor bearing mice. Further in vitro and in vivo assays showed the TGF- b/ID2/KDR signaling axis played an important role in driving differentiation of hematopoietic cells towards pro-angiogenic and pro-tumoral direction. ID2 and KDR in MDSCs promote angiogenesis and malignant transformation of glioma.