Metastases, or migration of cancers, are common and severe cancer complications. Although the 5-year survival rates of primary tumors have greatly improved, those of metastasis remain below 30%, highlighting the importance of investigating specific mechanisms and therapeutic approaches for metastasis. Microfluidic devices have emerged as a powerful platform for drug target identification and drug response screening and allow incorporation of complex interactions in the metastatic microenvironment as well as manipulation of individual factors. In this work, we review microfluidic devices that have been developed to study cancer cell migration and extravasation in response to mechanical (section 'Microfluidic investigation of mechanical factors in cancer cell migration'), biochemical (section 'Microfluidic investigation of biochemical signals in cancer cell invasion'), and cellular (section 'Microfluidic metastasis-on-a-chip models for investigation of cancer extravasation') signals. We highlight the device characteristics, discuss the discoveries enabled by these devices, and offer perspectives on future directions for microfluidic investigations of cancer metastasis, with the ultimate aim of identifying the essential factors for a 'metastasis-on-a-chip' platform to pursue more efficacious treatment approaches for cancer metastasis.

Bone metastasis is a common, yet serious, complication of breast cancer. Breast cancer cells that extravasate from blood vessels to the bone devastate bone quality by interacting with bone cells and disrupting the bone remodeling balance. Although exercise is often suggested as a cancer intervention strategy and mechanical loading during exercise is known to regulate bone remodeling, its role in preventing bone metastasis remains unknown. We developed a novel in vitro microfluidic tissue model to investigate the role of osteocytes in the mechanical regulation of breast cancer bone metastasis. Metastatic MDA-MB-231 breast cancer cells were cultured inside a 3D microfluidic lumen lined with human umbilical vein endothelial cells (HUVECs), which is adjacent to a channel seeded with osteocyte-like MLO-Y4 cells. Physiologically relevant oscillatory fluid flow (OFF) (1 Pa, 1 Hz) was applied to mechanically stimulate the osteocytes. Hydrogel-filled side channels in-between the two channels allowed real-time, bi-directional cellular signaling and cancer cell extravasation over 3 days. The applied OFF was capable of inducing intracellular calcium responses in osteocytes (82.3% cells responding with a 3.71 fold increase average magnitude). Both extravasation distance and percentage of extravasated side-channels were significantly reduced with mechanically stimulated osteocytes (32.4% and 53.5% of control, respectively) compared to static osteocytes (102.1% and 107.3% of control, respectively). This is the first microfluidic device that has successfully integrated stimulatory bone fluid flow, and demonstrated that mechanically stimulated osteocytes reduced breast cancer extravasation. Future work with this platform will determine the specific mechanisms involved in osteocyte mechanoregulation of breast cancer bone metastasis, as well as other types of cancer metastasis and diseases.

No abstract

No abstract

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.