RRC ID 60121
Author Li F, Kitajima S, Kohno S, Yoshida A, Tange S, Sasaki S, Okada N, Nishimoto Y, Muranaka H, Nagatani N, Suzuki M, Masuda S, Thai TC, Nishiuchi T, Tanaka T, Barbie DA, Mukaida N, Takahashi C.
Title Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion.
Journal Cancer Res
Abstract Cancer cell-intrinsic properties caused by oncogenic mutations have been well characterized; however, how specific oncogenes and tumor suppressors impact the tumor microenvironment (TME) is not well understood. Here, we present a novel non-cell-autonomous function of the retinoblastoma (RB) tumor suppressor in controlling the TME. RB inactivation stimulated tumor growth and neoangiogenesis in a syngeneic and orthotropic murine soft-tissue sarcoma model, which was associated with recruitment of tumor-associated macrophages (TAM) and immunosuppressive cells such as Gr1+CD11b+ myeloid-derived suppressor cells (MDSC) or Foxp3+ regulatory T cells (Treg). Gene expression profiling and analysis of genetically engineered mouse models revealed that RB inactivation increased secretion of the chemoattractant CCL2. Furthermore, activation of the CCL2-CCR2 axis in the TME promoted tumor angiogenesis and recruitment of TAMs and MDSCs into the TME in several tumor types including sarcoma and breast cancer. Loss of RB increased fatty acid oxidation (FAO) by activating AMP-activated protein kinase that led to inactivation of acetyl-CoA carboxylase, which suppresses FAO. This promoted mitochondrial superoxide production and JNK activation, which enhanced CCL2 expression. These findings indicate that the CCL2-CCR2 axis could be an effective therapeutic target in RB-deficient tumors. SIGNIFICANCE: These findings demonstrate the cell-nonautonomous role of the tumor suppressor retinoblastoma in the tumor microenvironment, linking retinoblastoma loss to immunosuppression.
Volume 79(15)
Pages 3903-3915
Published 2019-8-1
DOI 10.1158/0008-5472.CAN-18-3604
PII 0008-5472.CAN-18-3604
PMID 31189648
MeSH Animals Breast Neoplasms / metabolism Breast Neoplasms / pathology Cell Culture Techniques Cell Line, Tumor Chemokine CCL2 / biosynthesis Chemokine CCL2 / metabolism* Female Gene Expression Profiling / methods Humans Mice Mice, Inbred C57BL Mice, Knockout Receptors, CCR2 / metabolism Retinoblastoma Protein / deficiency Retinoblastoma Protein / metabolism* Soft Tissue Neoplasms / metabolism Soft Tissue Neoplasms / pathology Tumor Microenvironment Up-Regulation
IF 8.378
Times Cited 11
Human and Animal Cells RAW 264(RCB0535), THP-1(RCB1189), MCF7(RCB1904)