The influence of hemodynamic shear stress on circulating tumor cells

Metastasis, the spread of cancer and formation of secondary tumors, is a major contributor to the lethality of cancer. During process of traversing the body to the ultimate site of distant secondary tumors, cancer cells are faced with the biological and mechanical challenges of existing within the circulatory system. Cancer cells must deal with these difficulties without the evolutionary adaptations that sustain red and white blood cells. Due to this, it had been proposed that cancer cells from solid tumors would be susceptible to mechanical destruction via the physical forces in circulation. Contradictorily, it was shown that cancer cells are more mechanically resilient than non-cancerous cells to fluid shear stress (FSS), a physical stress present in circulation. This ability to resist mechanical destruction via FSS exposure was dependent on cellular mechanisms that underpin cellular mechanics.

Herein, I demonstrate that FSS exposure results in the activation of RhoA, a key regulator of cellular mechanics, and promotes downstream polymerization of F-actin and the activation of myosin. Inhibition of myosin activity resulted in a decrease in number of circulating tumor cells (CTCs), reduced the ability of CTCs to resist destruction by FSS exposure, and delayed the onset of metastatic disease. Moreover, FSS exposure also results in a RhoA dependent increase in the invasiveness of cancer cells. In addition to the alteration in cellular mechanics, FSS exposure increases metastatic potential and promotes changes in both gene expression and cellular metabolism that have been demonstrated to be pro-metastatic. Collectively, these studies demonstrate that the mechano-adaptation cancer cells undergo when exposed to FSS promote metastasis by reducing mechanical destruction and altering the biological state of the cells.