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Bone metastases, the migration of cancers to bone, occur in 65-80% of patients with advanced breast cancer. Metastasized cancer cells interact with cells such as the bone-resorbing osteoclasts to alter bone remodeling. Exercise, often suggested as an intervention for cancer patients, regulates bone remodeling via osteocytes. Osteocytes also signal to endothelial cells, which may affect cancer cell extravasation. Therefore, we hypothesize that mechanically stimulated osteocytes can regulate processes in breast cancer bone metastasis. To test this, we exposed osteocytes to oscillatory fluid flow in vitro using parallel-plate flow chambers. We observed that conditioned medium from flow-stimulated osteocytes increased migration (by 45%) and reduced apoptosis (by 12%) of breast cancer cells. Conditioned medium from osteoclasts conditioned in flowed osteocytes' conditioned medium reduced migration (by 47%) and increased apoptosis (by 55%) of cancer cells. Cancer cell trans-endothelial migration was reduced by 34% toward flowed osteocytes' conditioned medium. This difference was abolished with ICAM-1 or IL-6 neutralizing antibodies. Conditioned medium from endothelial cells conditioned in flowed osteocytes' conditioned medium increased cancer cell apoptosis by 29%. To summarize, this study demonstrated mechanically stimulated osteocytes' potential to affect breast cancer cells not only through direct signaling, but also through osteoclasts and endothelial cells. The anti-metastatic potential of the indirect signalings is particularly exciting since osteocytes are further away from metastasizing cancer cells than osteoclasts and endothelial cells. Future studies into the effect of bone mechanical loading on metastases and its mechanism will assist in designing cancer intervention programs that lowers the risk for bone metastases.

Spreading depression of Leão (SD) can be provoked by numerous nonspecific mechanical, electrical, and chemical stimuli. A similar, if not identical, phenomenon can be provoked by hypoxia. SD is characterized by drastic depolarization of neurons, severe reduction of membrane resistance, and redistribution of ions across cell membranes. Glial cells also depolarize but retain membrane resistance. Tetraethylammonium hastens the onset of hypoxic SD but reduces the sustained potential shift and K+ outflow from cells; 4-aminopyridine also accelerates SD but has no effect on the voltage shift. N-Methyl-D-aspartate receptor antagonists delay the onset of SD, while nickel and cobalt reduce the amplitude of SD-related redistribution of Ca2+. Yet, no specific blocker of SD has been found. Microdialysis of high-K+ solution in hippocampal CA1 region induces recurrent waves of SD propagating semi-independently in adjacent tissue layers, and a prolonged unstable depressed state that has not previously been described. Neither the release of K+ ions nor of glutamate is the unique agent of SD propagation. On the basis of recent findings we propose a hypothetical sequence of events that reconcile many of the previously seemingly paradoxical observations.

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