Cancer cell lines release glutamate into the extracellular environment

Abstract

Bone is one of the most frequent sites for metastasis of breast and prostate cancers. Bone metastases are associated with pathologic changes in bone turnover and severe pain. The mechanisms that trigger these effects are not well understood, but it is postulated that tumour cells release factors which interfere with signalling processes critical to bone homeostasis. We have identified that several cancer cell lines known to cause bone disruption in animal models of bone metastasis appear to secrete glutamate into their extracellular environment in vitro. Although these cells also express specific glutamate receptors, the implications of this potentially disruptive chemical signal are discussed in relation to normal glutamate-dependent communication processes in bone and a possible mechanistic connection is made between tumour cell glutamate release and the development of pathological changes in bone turnover.

Expression of metabotropic glutamate receptor 4 in osteosarcoma

“…While neoadjuvant chemotherapy has improved survival in patients with osteosarcoma, an effective targeted therapy is not yet available. Our findings taken together with those of previous studies indicate that the glutamate signaling pathway may serve as an important therapeutic target for osteosarcomas (19). However, further investigations are required to determine the potential of mGluR4 as a prognostic tool.…”

Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival

“…However, the rate of glycine and isoleucine uptake and glutamate secretion was markedly greater in the 3 prostate cancer cells compared with RWPE1. Increased glutamate secretion has been previously reported in cancer cells (20).…”

Physiological Roles of Non-Neuronal NMDA Receptors

“…Glutamate in turn encourages tumor growth and metastasis [124]. Non-CNS cancers also secrete glutamate in a manner likely mediated by Na + -independent cysteine/glutamate exchangers [125,126] and vesicular glutamate transporters (vGlut) [127]. Clinically, serum glutamate positively correlates with cancer progression and invasiveness [128], and the protumor effects of glutamate appear to be largely mediated by NMDARs.…”

“…GRIN2A and GRIN2B hypermethylation inversely correlated with GluN2A and GluN2B expression levels, and was associated with increased cancer cell proliferation and colony formation in vitro [143,144]. In [129,198] Small-cell GluN1; GluN2A-C [134] Connective tissue (muscle, bone) Sarcoma GluN1; GluN2A-D; GluN3A,B [198] Thyroid Carcinoma GluN1; GluN2B-D; GluN3A,B [198] Plasma cell Multiple myeloma GluN1; GluN2A-D [198] Colon/rectum Adenocarcinoma GluN1; GluN2A-D; GluN3A [129,138,198,199] T cell Leukemia GluN2A-D; GluN3A [198] Breast Adenocarcinoma GluN1; GluN2A-D; GluN3A [126,129,198] Ovaries Cystadenocarcinoma GluN1; GluN2B [202] Endometrioid adenocarcinoma GluN1; GluN2B [202] Clear-cell carcinoma GluN1; GluN2B [202] Megakaryoblasts Leukemic megarkaryoblasts GluN1; GluN2A-D; GluN3A,B [132] Oral cavity Squamous cell carcinoma GluN1 [140,141] Larynx Squamous cell carcinoma GluN1; GluN2A-D; GluN3A [136] Bone Osteosarcoma GluN1; GluN2A,B,D; GluN3A [203] accordance, ectopic GluN2B overexpression induced NMDAR-mediated apoptosis in gastric [144] and esophageal squamous cell carcinoma cells [143], and GluN2A overexpression stimulated colorectal cancer cell death [146]. In addition, whole-exome sequencing in malignant melanoma tumor samples revealed a significant prevalence of clustered mutations within GRIN2A functional domains, leading to truncated GluN2A [147], reduced NMDAR complex formation, and increased cancer cell growth, migration [148], and disease progression [149].…”