Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity

Haruki Horiguchi, Tsuyoshi Kadomatsu, Ryoma Kurahashi, Chiaki Hara, Keishi Miyata, Masaya Baba, Hironobu Osumi, Kazutoyo Terada, Kimi Araki, Toshiyuki Takai, Tomomi Kamba, W. Marston Linehan, Toshiro Moroishi, Yuichi Oike

Research output: Contribution to journalArticle

Abstract

Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing role of ANGPTL2 in host tumor microenvironmental cells. Furthermore, the syngeneic model showed that PDGFRα+ fibroblasts in the tumor microenvironment express abundant ANGPTL2 and contribute to tumor suppression. Moreover, host ANGPTL2 facilitates CD8+ T-cell cross-priming and enhances anti-tumor immune responses. Importantly, ANGPTL2 activates dendritic cells through PIR-B-NOTCH signaling and enhances tumor vaccine efficacy. Our study provides strong evidence that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.

Original languageEnglish
Pages (from-to)1641-1656
Number of pages16
JournalGenes & development
Volume33
Issue number23-24
DOIs
Publication statusPublished - 2019 Dec 1

Keywords

  • ANGPTL2
  • PirB
  • cancer immunity
  • dendritic cell

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Horiguchi, H., Kadomatsu, T., Kurahashi, R., Hara, C., Miyata, K., Baba, M., Osumi, H., Terada, K., Araki, K., Takai, T., Kamba, T., Linehan, W. M., Moroishi, T., & Oike, Y. (2019). Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity. Genes & development, 33(23-24), 1641-1656. https://doi.org/10.1101/gad.329417.119