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.

• Authors: Haruki Horiguchi, Tsuyoshi Kadomatsu, Keishi Miyata, Kazutoyo Terada, Michio Sato, Daisuke Torigoe, Jun Morinaga, Toshiro Moroishi, Yuichi Oike
• Journal: Oncogene (Oncogene) Vol. 40 Issue 1 Pg. 55-67 (01 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 33051596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiopoietin-Like Protein 2
• Angiopoietin-like Proteins
• Angptl2 protein, mouse
• NF-kappa B
• Dextran Sulfate
• Azoxymethane

Topics

• Angiopoietin-Like Protein 2
• Angiopoietin-like Proteins (genetics)
• Animals
• Azoxymethane (adverse effects)
• CD4-Positive T-Lymphocytes (metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Colitis (chemically induced, complications, genetics)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Gene Knockout Techniques
• Intestinal Neoplasms (chemically induced, genetics, pathology)
• Macrophages (metabolism)
• Mice
• NF-kappa B (metabolism)
• Signal Transduction
• Tumor Microenvironment