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Open Access Highly Accessed Research article

Endothelial cell-derived interleukin-6 regulates tumor growth

Kathleen G Neiva1, Kristy A Warner1, Marcia S Campos1, Zhaocheng Zhang1, Juliana Moren1, Theodora E Danciu2 and Jacques E Nör13456*

Author Affiliations

1 Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109-1078, USA

2 Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109-1078, USA

3 Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan 48109-1078, USA

4 Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-1078, USA

5 Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109-1078, USA

6 Angiogenesis Research Laboratory, University of Michigan School of Dentistry, 1011 N. University Rm. 2309, Ann Arbor, MI 48109-1078, USA

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BMC Cancer 2014, 14:99  doi:10.1186/1471-2407-14-99

Published: 17 February 2014

Abstract

Background

Endothelial cells play a complex role in the pathobiology of cancer. This role is not limited to the making of blood vessels to allow for influx of oxygen and nutrients required for the high metabolic demands of tumor cells. Indeed, it has been recently shown that tumor-associated endothelial cells secrete molecules that enhance tumor cell survival and cancer stem cell self-renewal. The hypothesis underlying this work is that specific disruption of endothelial cell-initiated signaling inhibits tumor growth.

Methods

Conditioned medium from primary human dermal microvascular endothelial cells (HDMEC) stably transduced with silencing RNA for IL-6 (or controls) was used to evaluate the role of endothelial-derived IL-6 on the activation of key signaling pathways in tumor cells. In addition, these endothelial cells were co-transplanted with tumor cells into immunodefficient mice to determine the impact of endothelial cell-derived IL-6 on tumor growth and angiogenesis.

Results

We observed that tumor cells adjacent to blood vessels show strong phosphorylation of STAT3, a key mediator of tumor progression. In search for a possible mechanism for the activation of the STAT3 signaling pathway, we observed that silencing interleukin (IL)-6 in tumor-associated endothelial cells inhibited STAT3 phosphorylation in tumor cells. Notably, tumors vascularized with IL-6-silenced endothelial cells showed lower intratumoral microvessel density, lower tumor cell proliferation, and slower growth than tumors vascularized with control endothelial cells.

Conclusions

Collectively, these results demonstrate that IL-6 secreted by endothelial cells enhance tumor growth, and suggest that cancer patients might benefit from targeted approaches that block signaling events initiated by endothelial cells.

Keywords:
Cervical Cancer; Signaling pathways; Molecular targeted therapy; STAT3