Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis

Abstract

Previous studies show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts. However, we recently reported that host ANGPTL2 also shows tumor suppressive activity by enhancing dendritic cell-mediated CD8+ T cell anti-tumor immune responses in mouse kidney cancer and murine syngeneic models. However, mechanisms underlying ANGPTL2-mediated tumor suppression are complex and not well known. Here, we investigated ANGPTL2 tumor suppressive function in chemically-induced intestinal tumorigenesis. ANGPTL2 deficiency enhanced intestinal tumor growth in an experimental mouse colitis-associated colon cancer (CAC) model. Angptl2-deficient mice also showed a decrease not only in CD8+ T cell responses but in CD4+ T cell responses during intestinal tumorigenesis. Furthermore, we show that stroma-derived ANGPTL2 can activate the myeloid immune response. Notably, ANGPTL2 drove generation of immunostimulatory macrophages via the NF-κB pathway, accelerating CD4+ T helper 1 (Th1) cell activation. These findings overall provide novel insight into the complex mechanisms underlying ANGPTL2 anti-tumor function in cancer pathology.

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Fig. 1: ANGPTL2 deficiency enhances CAC progression.
Fig. 2: ANGPTL2 deficiency decreases T cell immune responses.
Fig. 3: Angptl2-deficient mice show attenuated myeloid immune responses.
Fig. 4: ANGPTL2 in WT colon is expressed predominantly by intestinal myofibroblasts.
Fig. 5: ANGPTL2 promotes monocyte differentiation into Ly6Chigh macrophages via NF-κB signaling.
Fig. 6: ANGPTL2-mediated macrophage activation induces IFN-γ production by CD4+ T cells.
Fig. 7: Model proposing an anti-tumorigenic role of ANGPTL2 during injury-induced colorectal tumorigenesis.

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Acknowledgements

We thank Kiyoka Tabu, Noriko Shirai, and Sayomi Iwaki for technical assistance. This work was supported by the Scientific Research Fund of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (grant 18K07236 to TK, grant 18K15246 to HH), the Core Research for Evolutional Science and Technology (CREST) program of the Japan Science and Technology Agency (JST) (grant 13417915 to YO), the CREST program of the Japan Agency for Medical Research and Development (AMED) (grant JP18gm0610007 to YO), and the Takeda Science Foundation (HH, TK).

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HH designed the study, performed and analyzed most of experiments, and wrote the paper. TK designed the study and wrote the paper. KM provided Angptl2 mutant mice. KT provided recombinant ANGPTL2 protein. MS and DT discussed the data. JM assisted with statistical analysis. TM designed and supervised the study, and wrote the paper. YO coordinated, designed, and supervised the study, and wrote the paper. All authors discussed the data and commented on the paper.

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Correspondence to Tsuyoshi Kadomatsu or Yuichi Oike.

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Horiguchi, H., Kadomatsu, T., Miyata, K. et al. Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis. Oncogene (2020). https://doi.org/10.1038/s41388-020-01505-7

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