Speyer Cecilia L, Hachem Ali H, Assi Ali A, Johnson Jennifer S, DeVries John A, Gorski David H
Tumor Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America; Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
University of Michigan, Dearborn, Michigan, United States of America.
PLoS One. 2014 Mar 14;9(3):e88830. doi: 10.1371/journal.pone.0088830. eCollection 2014.
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.
代谢型谷氨酸受体（mGluRs）通常在中枢神经系统中表达，在那里它们介导神经元兴奋性和神经递质释放。某些癌症，包括黑色素瘤和神经胶质瘤，表达多种mGluR亚型，这些亚型被认为在疾病进展中起作用。最近，我们在乳腺癌中检测到代谢型谷氨酸受体-1（基因：GRM1；蛋白：mGluR1），并发现它在细胞增殖和肿瘤生长的调节中发挥作用。除癌细胞外，脑内皮细胞也表达mGluR1。鉴于这些研究，并且由于血管生成既是癌症预后的一个指标，与较差的预后相关，又是一个潜在的治疗靶点，我们探讨了mGluR1在介导内皮细胞（EC）增殖和肿瘤诱导的血管生成中的潜在作用。在各种类型的人内皮细胞中检测到GRM1和mGluR1，并且使用mGluR1特异性抑制剂或shRNA沉默，我们证明了内皮细胞生长和基质胶管形成依赖于mGluR1信号传导。此外，在小鼠基质胶海绵植入模型以及小鼠肿瘤模型中，mGluR1活性的丧失导致血管生成减少。这些结果表明mGluR1在乳腺癌中作为促血管生成因子以及肿瘤进展的介质发挥作用。它们还表明mGluR1作为乳腺癌抗血管生成治疗的潜在新分子靶点。
