Editors' ChoiceCancer

A workout plan to prevent metastasis

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Science Translational Medicine  12 Jun 2019:
Vol. 11, Issue 496, eaax9564
DOI: 10.1126/scitranslmed.aax9564

Abstract

Stimulating osteocytes with mechanical forces representative of exercise reduces breast cancer extravasation in a microfluidic model.

Metastasis is the primary cause of cancer-related death, with bone being the most prevalent metastatic site for patients suffering from breast or prostate cancer. The bone microenvironment contains a multitude of cell lineages: bone-forming osteoblasts; bone-resorbing osteoclasts; and osteocytes, which are bone cells embedded in the mineralized matrix, that are activated to remodel bone in response to exercise-induced mechanical loading. Clinicians recommend exercise to cancer patients undergoing treatment because it results in improved quality of life. In mouse models, exercise also decreases cancer growth and metastatic seeding in the lungs. However, it was unclear whether and how the increased mechanical stress on the bone cells would affect cancer metastasis to bone.

Mei and colleagues have developed a reductionist microfluidic device to assess how mechanotransduction to osteocytes affects breast cancer extravasation. To model the mechanical forces induced by exercise, physiologically relevant oscillating fluid flow inducing shear stress was applied to murine osteocyte cells embedded in a microfluidic channel. Human umbilical vein endothelial cells were seeded in a parallel microfluidic channel representing a vascular lumen. Human breast cancer cells were injected into the endothelial channel, and extravasation into side channels and chemotaxis toward the osteocyte channel were measured. Encapsulation of osteocytes with osteoclast-derived conditioned medium increased breast cancer cell extravasation distance, whereas exposure of osteocytes to shear stress reduced breast cancer cell migration from the endothelial lumen. Thus, breast cancer extravasation was decreased toward mechanically stimulated osteocytes, indicating that exercise may help prevent metastatic seeding of the bone.

Further studies increasing the complexity of the microfluidic device will be required to prove that shear stress–induced changes in osteocytes prevent bone colonization by cancer cells. The reductionist model used in this study did not include fluid flow through the endothelial lumen, which would affect the extravasation of cancer cells. Further, in the native bone marrow, matrix-embedded osteocytes are further separated from colonizing cancer cells by osteoblasts, osteoclasts, mesenchymal stem cells, and hematopoietic cells—all of which will also respond to osteocyte-secreted proteins and growth factors. Because earlier literature had focused on fatigue and quality of life after exercise regimens in cancer patients, long-term clinical studies are needed to assess the effects of exercise during treatment on disease-free, progression-free, or overall survival in cancer patients.

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