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.

Fatigue loading causes a spatial distribution of osteocyte apoptosis co‐localized with bone resorption spaces peaking around microdamage sites. Since osteocytes have been shown to regulate osteoclast formation and activity, we hypothesize that osteocyte apoptosis regulates osteoclastogenesis. In this study, we used serum‐starvation to mimic reduced nutrient transport in microdamaged bone and induce apoptosis in MLO‐Y4 osteocyte‐like cells; conditioned medium was used to apply soluble factors released by apoptotic osteocytes (aOCY) to healthy non‐apoptotic MLO‐Y4 cells. Osteoclast precursor (RAW264.7 monocyte) migration and differentiation were assessed in the presence of conditioned media (CM) from: (A) aOCY, (B) osteocytes treated with apoptosis conditioned medium (i.e., healthy osteocytes in the presence of apoptosis cues; apoptosis CM‐treated osteocytes (atOCY)), and (C) osteocytes treated with non‐apoptosis conditioned medium (i.e., healthy osteocytes in the absence of apoptosis cues; non‐apoptosis CM‐treated osteocytes (natOCY)). Receptor activator for nuclear factor‐κB ligand (RANKL), macrophage colony stimulating factor (M‐CSF), vascular endothelial growth factor (VEGF) and osteoprotegerin (OPG) mRNA, and protein expression were measured. Our findings indicate that soluble factors released by aOCY and atOCY promoted osteoclast precursor migration (up to 64% and 24% increase, respectively) and osteoclast formation (up to 450% and 265% increase, respectively). Osteoclast size increased up to 233% in the presence of aOCY and atOCY CM. Recruitment, formation and size were unaltered by natOCY. RANKL mRNA and protein expression were upregulated only in aOCY, while M‐CSF and VEGF increased in atOCY. Addition of RANKL‐blocking antibody abolished aOCY‐induced osteoclast precursor migration and osteoclast formation. VEGF and M‐CSF blocking antibodies abolished atOCY‐induced osteoclastogenesis. These findings suggest that aOCY directly and indirectly (through atOCY) initiate targeted bone resorption by regulating osteoclast precursor recruitment and differentiation. J. Cell. Biochem. 112: 2412–2423, 2011.

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.