Open Access

ARTICLE

Hypoxia enhances CXCR4 expression in human microvascular endothelial cells and human melanoma cells

Evemie Schutyser^1,2, Yingjun Su², Yingchun Yu², Mieke Gouwy¹, Snjezana Zaja-Milatovic², Jo Van Damme¹, Ann Richmond²

1 Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Belgium
2 Departments of Veterans Affairs and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

* Corresponding Author: J. Van Damme,

European Cytokine Network 2007, 18(2), 59-70. https://doi.org/10.1684/ecn.2007.0087

Accepted 11 April 2007;

Abstract

The influence of environmental factors (cytokines, matrix components, serum factors and O₂ level) on expression of receptors for angiogenic versus angiostatic CXC chemokines in human microvascular endothelial cells has not been extensively investigated. Our semi-quantitative RT-PCR analysis demonstrated that TNF-α and IFN-γ repressed CXCR4 mRNA levels in immortalized human microvascular endothelial HMEC-1 cells after 4 h, whereas only TNF-α displayed inhibitory activity in primary human microvascular endothelial cells (HMVEC). CXCR4 mRNA expression was not affected by VEGF, GM-CSF, IL-1β or various basal membrane matrix components, but was significantly up-regulated after serum starvation and/or hypoxic treatment of the microvascular endothelial cells. The alternative CXCL12 receptor, CXCR7/RDC1, was also up-regulated by hypoxia in HMEC-1 cells, although less consistently than CXCR4. Furthermore, hypoxia and serum starvation were required for cell surface display of CXCR4 and CXCL12 induction of ERK activation in HMEC-1 cells. In contrast, CXCR2 and CXCR3 mRNA levels remained, respectively, low and undetectable under all the conditions tested, and surface expression of CXCR2, CXCR3 and CXCR7 on the HMEC- 1 cells could not be demonstrated by FACS. In the human SK-MEL-5 melanoma cell line, CXCR4 mRNA expression was also increased under hypoxic conditions, whereas CXCR2 mRNA levels remained low and levels of CXCR3 and CXCR7 were undetectable. However, immunohistochemical staining of human metastatic melanoma sections demonstrated that CXCR2, CXCR3, CXCR4 and CXCR7 are expressed on tumor cells and, to a lesser extent, on endothelial cells. These results demonstrate that the tumor microenvironment regulates chemokine receptor expression through both cytokine and oxygen levels.

---

Keywords

---