Resistance to Fluid Shear Stress Is a Conserved Biophysical Property of Malignant Cells

Abstract

During metastasis, cancer cells enter the circulation in order to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood. A longstanding view is that circulating cancer cells derived from solid tissues may be susceptible to damage from hemodynamic shear forces, contributing to metastatic inefficiency. Here we report that compared to non-transformed epithelial cells, transformed cells are remarkably resistant to fluid shear stress (FSS) in a microfluidic protocol, exhibiting a biphasic decrease in viability when subjected to a series of millisecond pulses of high FSS. We show that magnitude of FSS resistance is influenced by several oncogenes, is an adaptive and transient response triggered by plasma membrane damage and requires extracellular calcium and actin cytoskeletal dynamics. This novel property of malignant cancer cells may facilitate hematogenous metastasis and indicates, contrary to expectations, that cancer cells are quite resistant to destruction by hemodynamic shear forces.

Modulation of rotation-induced lift force for cell filtration in a low aspect ratio microchannel

“…While the shear in the main channel can be the cause of cell loss, the reduced viability is most likely the result of the much smaller outlet branches (w ¼ 32 lm) where s w ¼ 199 dyn/cm 2 despite only 1/3 of the input flow rate. The dependence of cell viability on shear stress we find here is similar to the work by Barnes et al 39 using prostate cells (PC-3). Nevertheless, 83% viability is sufficiently high considering the fragile nature of the LNCaP cells.…”

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

“…KPC cells were primed with Fasudil and exposed to controlled shear stress as previously described (Fig. 6F) (62) and then plated on CDMs to measure their ability to attach, survive, or proliferate after shear stress. Cell attachment on CDMs and cell growth were reduced upon treatment with Fasudil, with a concomitant increase in apoptosis (Fig.…”

Tissue mechanics regulate brain development, homeostasis and disease

“…During metastasis, cancer cells experience a wide range of forces when moving from one microenvironment to the next, and the ability to navigate and endure these forces greatly influences the successful survival and colonization of the metastatic cell. Although tissue-level stiffening of tumors is common, the increased compliance of individual cells is associated with metastatic progression and tumor aggression due to an enhanced ability to invade through basement membranes and ECM, and pass through the circulatory system (Barnes et al, 2012;Cross et al, 2007). Convincing evidence for mechanical regulation of solid tumors is quickly accumulating, particularly in the context of breast cancer (Pickup et al, 2014), and studies on the interplay between brain tissue mechanics and tumor biology are increasing as well.…”