For example glutamate is increasingly recognized as one of t

For example, glutamate is increasingly recognized as one of the important dysregulated signaling molecules in cancer biology, especially in the context of bone metastasis. Commonly recognized as an excitatory neurotransmitter necessary for normal SCR7 function, glutamate is also intimately involved in bone metabolism in both health and diseased bone [34]. Multiple cancer cell lines are known to secrete glutamate into the extracellular environment [35]. In vitro models have shown that its secretion by cancer cell lines stimulated osteoblast differentiation, while inhibition of glutamate release led to reduction of the osteoclast population [36]. Specific glutamate receptors present on osteoclasts have been identified, and modulation of these receptors can inhibit glutamate release and bone resorption [37]. Glutamate is also associated with the perception and transmission of pain. Multiple studies involving subcutaneous administration of glutamate to healthy volunteers revealed glutamate to be a potent dose-dependent inducer of the pain response [38,39]. Given its secretion by cancer cells, tumor-derived glutamate may be involved in the generation or maintenance of cancer-induced bone pain, through direct stimulation of perception of pain or its disruptive effect upon bone homeostasis in the presence of bone metastases. Lastly, glutamate may also contribute to cancer-associated depression. Major and minor depression can be seen in over one third of cancer patients [40], a rate that is far higher than in the general population [41]. Abnormalities in glutamate levels have been observed in multiple areas of the brain in patients with depression [42]. Compellingly, the glutamate receptor antagonist ketamine has been shown in multiple small studies to produce anti-depressive effects in patients [43]. Whether direct links exist between tumor-secreted glutamate and depression is currently not known but warrants further investigation.
Summary The BONUS conference continues to be a forum that attracts oncologists, basic scientists, and other professionals interested in bone health in cancer. This year׳s meeting reviewed our current understanding of bone biology and metastasis, as well as ongoing research in the field. What is evident is that we have likely maximized the benefits that patients will receive from current bone-targeted therapies and that the gains from increasingly potent agents while statistically significant are clinically modest [10,44]. If progress in this area is going to be made we need to use the new knowledge we are generating around the complex interactions that occur in bone to develop new treatment strategies. Ultimately we all hope that this will also enhance our efforts at trying to stop breast cancer from spreading to the bones in the first case.
Conflict of interest statement
Acknowledgments Funding for the BONUS 8 meeting comes in the form of unrestricted educational grants from Amgen, Novartis, Roche and, Janssen. These companies had no input into this Commentary.
Introduction External beam radiotherapy (RT) is a well-established and efficacious method of palliating painful bone metastases [1,2]. Patients with bone metastases are at high risk for skeletal-related events such as pathologic fractures or spinal cord compression [3]. This may affect the pain response following RT and lower the quality of life in these patients [4]. However, limited data exist on the local disease control and the incidence of fractures after conventional fractionated RT to the spine [2,4–8]. Furthermore, the impact of fractures on pain response is essentially unknown. Magnetic resonance imaging (MRI) is the modality of choice for the diagnosis and follow-up of cancer patients with spinal metastases (SM). Only a few studies have evaluated pain response and imaging features after RT in patients with SM, and the findings have been inconsistent [9–11]. Hence, it is important to determine to what extent the RT response rate in SM is correlated with the presence of skeletal complications such as fractures or compression syndromes. Thus, the aim of this study was to evaluate the irradiated metastatic lesions and the rate of local tumor control using repeated MRI and to compare the imaging findings with pain response after RT in patients with SM from breast cancer.