CD47 deficiency in tumor stroma promotes tumor progression by enhancing angiogenesis.
CD47 is a transmembrane protein that functions as a receptor for thrombospondin-1 (TSP1) and a ligand for inhibitory receptor signal-regulatory protein-α (SIRPα). Blocking the interaction between CD47 on tumor cells and SIRPα on macrophages has been shown to induce antitumor responses. Here we investigated the role of CD47 expression in tumor stroma in tumorigenesis by comparing tumor growth in wild-type (WT) and CD47-deficient mice after subcutaneous injection of syngeneic prostate cancer cells. We found that CD47 deficiency in tumor stromal endothelial cells enhances angiogenesis, leading to suppressed tumor necrosis formation and accelerated tumor progression. Tumors from CD47-deficient mice also showed improved vascular integrity and stability, as well as increased expression of vascular endothelial growth factor (VEGF)-A and VEGF receptor 2 (VEGFR2) compared to those from WT mice. Moreover, reduced macrophage recruitment, likely due to decreased TSP1 production, was detected in tumors from CD47-deficient mice. Our results indicate that although treatment with antibody against CD47 induces antitumor immune responses by blocking the inhibitory CD47-SIRPα signaling, this treatment may also potentially promote tumor progression by blocking CD47 signaling in tumor stromal endothelial cells.
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Lu
L
Gao
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Kexin
K
Chen
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Qi
Q
Gao
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Xiaodan
X
Wang
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Jian
J
Sun
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.|Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, USA.
Yong-Guang
YG
Yang
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D017154:Stromal Cells / Q000502:physiology*
D000943:Antigens, Differentiation; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051928:CD47 Antigen; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; C481348:SPZ1 protein, human
CD47; SIRPα; TSP1; angiogenesis; tumorigenesis