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Genes Dev. 2019 Dec 1;33(23-24):1641-1656. doi: 10.1101/gad.329417.119. Epub 2019 Nov 14.

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

Author information

1
Department of Molecular Genetics, Graduate school of Medical science, Kumamoto University, Kumamoto 860-8556, Japan.
2
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
3
Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
4
Department of Urology, Graduate school of Medical science, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
5
International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan.
6
Department of Thoracic Surgery, Graduate school of Medical science, Kumamoto University, Kumamoto 860-8556, Japan.
7
Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
8
Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
9
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
10
Department of Molecular Enzymology, Faculty of Life sciences, Kumamoto University, Kumamoto 860-8556, Japan.
11
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan.
12
Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo 100-0004, Japan.

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.

KEYWORDS:

ANGPTL2; PirB; cancer immunity; dendritic cell

PMID:
31727773
DOI:
10.1101/gad.329417.119

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