Deletion of IL-33R attenuates VEGF expression and enhances necrosis in mammary carcinoma

• Published in: Oncotarget Vol. 7; no. 14; pp. 18106 - 18115
• Main Authors: Milosavljevic, Milos Z, Jovanovic, Ivan P, Pejnovic, Nada N, Mitrovic, Slobodanka L J, Arsenijevic, Nebojsa N, Simovic Markovic, Bojana J, Lukic, Miodrag L
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 05-04-2016
• Subjects: Animals; Breast Neoplasms - pathology; Cell Line, Tumor; Female; Humans; Interleukin-33 - metabolism; Mammary Neoplasms, Animal - blood supply; Mammary Neoplasms, Animal - pathology; Mice; Mice, Inbred BALB C; Mice, Knockout; Microvessels - pathology; Middle Aged; Necrosis - genetics; Necrosis - pathology; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Neovascularization, Pathologic - pathology; Receptors, Interleukin - genetics; Receptors, Interleukin - metabolism; Research Paper; Vascular Endothelial Growth Factor A - metabolism; breast neoplasm; necrosis; IL-33; IL-33R; neoangiogenesis
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.7635

Interleukin-33 (IL-33)/IL-33 receptor (IL-33R, ST2) signaling pathway promotes mammary cancer growth and metastasis by inhibiting anti-tumor immunity. However, the role of IL-33/IL-33R axis in neoangiogenesis and tumor necrosis is not elucidated. Therefore, the aim of this study was to investigate the role of IL-33/IL-33R axis in mammary tumor necrosis. Deletion of IL-33R (ST2) gene in BALB/c mice enhanced tumor necrosis and attenuated tumor growth in 4T1 breast cancer model, which was associated with markedly decreased expression of vascular endothelial growth factor (VEGF) and IL-33 in mammary tumor cells. We next analyzed IL-33, IL-33R and VEGF expression and microvascular density (MVD) in breast tumors from 40 female patients with absent or present tumor necrosis. We found significantly higher expression of IL-33, IL-33R and VEGF in breast cancer tissues with absent tumor necrosis. Both, IL-33 and IL-33R expression correlated with VEGF expression in tumor cells. Further, VEGF expression positively correlated with MVD in perinecrotic zone. Taking together, our data indicate that IL-33/IL-33R pathway is critically involved in mammary tumor growth by facilitating expression of pro-angiogenic VEGF in tumor cells and attenuating tumor necrosis. These data add an unidentified mechanism by which IL-33/IL-33R axis facilitates tumor growth.