Retinoblastoma inactivation induces a protumoral microenvironment via enhanced CCL2 secretion

Fengkai Li, Shunsuke Kitajima, Susumu Kohno, Akiyo Yoshida, Shoichiro Tange, Soichiro Sasaki, Nobuhiro Okada, Yuuki Nishimoto, Hayato Muranaka, Naoko Nagatani, Misa Suzuki, Sayuri Masuda, Tran C. Thai, Takumi Nishiuchi, Tomoaki Tanaka, David A. Barbie, Naofumi Mukaida, Chiaki Takahashi

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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.

Original languageEnglish
Pages (from-to)3903-3915
Number of pages13
JournalCancer Research
Volume79
Issue number15
DOIs
Publication statusPublished - Aug 1 2019

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Retinoblastoma
Tumor Microenvironment
Neoplasms
Sarcoma
Fatty Acids
Acetyl-CoA Carboxylase
AMP-Activated Protein Kinases
Chemotactic Factors
Gene Expression Profiling
Regulatory T-Lymphocytes
Immunosuppressive Agents
Oncogenes
Superoxides
Immunosuppression
Macrophages
Breast Neoplasms
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Li, F., Kitajima, S., Kohno, S., Yoshida, A., Tange, S., Sasaki, S., ... Takahashi, C. (2019). Retinoblastoma inactivation induces a protumoral microenvironment via enhanced CCL2 secretion. Cancer Research, 79(15), 3903-3915. https://doi.org/10.1158/0008-5472.CAN-18-3604

Retinoblastoma inactivation induces a protumoral microenvironment via enhanced CCL2 secretion. / 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.

In: Cancer Research, Vol. 79, No. 15, 01.08.2019, p. 3903-3915.

Research output: Contribution to journalArticle

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 2019, 'Retinoblastoma inactivation induces a protumoral microenvironment via enhanced CCL2 secretion', Cancer Research, vol. 79, no. 15, pp. 3903-3915. https://doi.org/10.1158/0008-5472.CAN-18-3604
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. / Retinoblastoma inactivation induces a protumoral microenvironment via enhanced CCL2 secretion. In: Cancer Research. 2019 ; Vol. 79, No. 15. pp. 3903-3915.
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AU - Kitajima, Shunsuke

AU - Kohno, Susumu

AU - Yoshida, Akiyo

AU - Tange, Shoichiro

AU - Sasaki, Soichiro

AU - Okada, Nobuhiro

AU - Nishimoto, Yuuki

AU - Muranaka, Hayato

AU - Nagatani, Naoko

AU - Suzuki, Misa

AU - Masuda, Sayuri

AU - Thai, Tran C.

AU - Nishiuchi, Takumi

AU - Tanaka, Tomoaki

AU - Barbie, David A.

AU - Mukaida, Naofumi

AU - Takahashi, Chiaki

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