Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 15; pp. 3903 - 3915
• Main Authors: Li, Fengkai, Kitajima, Shunsuke, Kohno, Susumu, Yoshida, Akiyo, Tange, Shoichiro, Sasaki, Soichiro, Okada, Nobuhiro, Nishimoto, Yuuki, Muranaka, Hayato, Nagatani, Naoko, Suzuki, Misa, Masuda, Sayuri, Thai, Tran C, Nishiuchi, Takumi, Tanaka, Tomoaki, Barbie, David A, Mukaida, Naofumi, Takahashi, Chiaki
• Format: Journal Article
• Language: English
• Published: United States 01.08.2019
• Subjects: 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-18-3604

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.