Alterations in cancer cell mechanical properties after fluid shear stress exposure: a micropipette aspiration study

Abstract

Over 90% of cancer deaths result not from primary tumor development, but from metastatic tumors that arise after cancer cells circulate to distal sites via the circulatory system. While it is known that metastasis is an inefficient process, the effect of hemodynamic parameters such as fluid shear stress (FSS) on the viability and efficacy of metastasis is not well understood. Recent work has shown that select cancer cells may be able to survive and possibly even adapt to FSS in vitro. The current research seeks to characterize the effect of FSS on the mechanical properties of suspended cancer cells in vitro. Nontransformed prostate epithelial cells (PrEC LH) and transformed prostate cancer cells (PC-3) were used in this study. The Young’s modulus was determined using micropipette aspiration. We examined cells in suspension but not exposed to FSS (unsheared) and immediately after exposure to high (6,400 dyn/cm2) and low (510 dyn/cm2) FSS. The PrEC LH cells were ~140% stiffer than the PC-3 cells not exposed to FSS. Post-FSS exposure, there was an increase of ~77% in Young’s modulus after exposure to high FSS and a ~47% increase in Young’s modulus after exposure to low FSS for the PC-3 cells. There was no significant change in the Young’s modulus of PrEC LH cells post-FSS exposure. Our findings indicate that cancer cells adapt to FSS, with an increased Young’s modulus being one of the adaptive responses, and that this adaptation is specific only to PC-3 cells and is not seen in PrEC LH cells. Moreover, this adaptation appears to be graded in response to the magnitude of FSS experienced by the cancer cells. This is the first study investigating the effect of FSS on the mechanical properties of cancer cells in suspension, and may provide significant insights into the mechanism by which some select cancer cells may survive in the circulation, ultimately leading to metastasis at distal sites. Our findings suggest that biomechanical analysis of cancer cells could aid in identifying and diagnosing cancer in the future.

Melanoma in the Eyes of Mechanobiology

“…Lee et al (2017) showed that mechanical forces exerted by the fluid flow regulate cell behavior, being crucial for the metastasis process . Chivukula et al (2015) also demonstrated that cancer prostate cells may be able to adapt to the fluid shear stress (FSS). Micropipette aspiration was used to measure the Young's modulus of prostate epithelial and prostate cancer cells.…”

Investigating the effect of fluid shear stress on the failure of cancer cell membranes

“…It has already been discussed that cancer cells have higher viability rates after fluid shear stress exposure. It has also been shown that cancer cells exhibit different mechanical properties compared to non-cancerous cells before and after exposure to shear stress (Chivukula et al, 2015). Before exposure to shear stress, the elastic modulus of epithelial cells in this study was about 2.4 times that of the cancer cells.…”

“…The occlusion of blood flow in the capillary increases the pressure gradient across the cell, potentially leading to membrane failure. This hypothesis seems unlikely; micropipette and microfluidic experiments can apply high pressure gradients across cancer cells without causing membrane failure (Chivukula et al, 2015). The highly parallel nature of capillary beds is also a protection against large pressure buildup due to occlusion.…”

“…Are the pressures and stresses experienced in the circulatory system enough to rupture the cells? Does the increased stiffness after shear stress exposure demonstrated by Chivukula indicate that cancer cells are less likely to rupture after shear exposure (Chivukula et al, 2015)? Does membrane rupture correlate with a high localized membrane tension?…”

“…Figure 5: Parameters measured during micropipette aspiration. Reproduced without permission from (Chivukula, Krog, Nauseef, Henry, & Vigmostad, 2015) hydrostatic pressure at the tip of the pipette. The system is illustrated in Figure 4.…”