Deletion of IL-33R attenuates VEGF expression and enhances necrosis in mammary carcinoma
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Milos Z. Milosavljevic1,*, Ivan P. Jovanovic2,*, Nada N. Pejnovic2, Slobodanka L. J. Mitrovic1, Nebojsa N. Arsenijevic2, Bojana J. Simovic Markovic2 and Miodrag L. Lukic2
1 Department of Pathology, University Medical Center Kragujevac, Kragujevac, Serbia
2 Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
* These authors have contributed equally to this work
Miodrag L. Lukic, email:
Keywords: breast neoplasm, IL-33, IL-33R, neoangiogenesis, necrosis
Received: October 26, 2015 Accepted: February 11, 2016 Published: February 23, 2016
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.
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