Oncotarget

Research Papers:

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

Milos Z. Milosavljevic, Ivan P. Jovanovic, Nada N. Pejnovic, Slobodanka L. J. Mitrovic, Nebojsa N. Arsenijevic, Bojana J. Simovic Markovic and Miodrag L. Lukic _

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Oncotarget. 2016; 7:18106-18115. https://doi.org/10.18632/oncotarget.7635

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Abstract

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

Correspondence to:

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

Abstract

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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