Abstract
Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer prognosis and a potential therapeutic target, we explored a potential role for mGluR1 in mediating endothelial cell (EC) proliferation and tumor-induced angiogenesis. GRM1 and mGluR1 were detected in various types of human ECs and, using mGluR1-specific inhibitors or shRNA silencing, we demonstrated that EC growth and Matrigel tube formation are dependent on mGluR1 signaling. In addition, loss of mGluR1 activity leads to reduced angiogenesis in a murine Matrigel sponge implant model as well as a murine tumor model. These results suggest a role for mGluR1 in breast cancer as a pro-angiogenic factor as well as a mediator of tumor progression. They also suggest mGluR1 as a potential new molecular target for the anti-angiogenic therapy of breast cancer.
Highlights
Angiogenesis is critical for normal physiological processes, including wound healing, embryonic development, and the menstrual cycle
Results mGluR1 is expressed in human endothelial cells and regulates cell proliferation
To determine whether mGluR1 is expressed in human endothelial cell (EC), we assessed several primary ECs (HDEC, human umbilical vein endothelial cells (HUVEC), human pulmonary microvascular endothelial cells (HLEC)) or cell lines (HMEC-1) for mGluR1 by Western blot analysis. mGluR1 was detected in all four EC types with higher levels expressed in HUVEC and HMEC-1 (Fig. 1A–B)
Summary
Angiogenesis is critical for normal physiological processes, including wound healing, embryonic development, and the menstrual cycle. Tumors are critically dependent upon their ability to hijack the normal physiologic process of angiogenesis and thereby induce the ingrowth of blood vessels from the host in order to grow, invade, and metastasize [1,2]. Numerous studies have reported a correlation between increased angiogenesis and poor prognosis in various cancers [7,8], and inhibiting tumor-induced angiogenesis has emerged over the last decade as a promising strategy for cancer therapy. Bevacizumab, a humanized mouse monoclonal antibody to VEGF that is currently the most commonly used antiangiogenic therapy for cancer, is expensive, must be given intravenously, and produces side effects of hypertension, hemorrhage and even intestinal perforation, among others [10,11]. Tumors can overcome bevacizumab by producing more VEGF, leading to resistance. [11]
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