Mechanotransduction in Endothelial Cells in Vicinity of Cancer Cells.

Abstract

Introduction-Local hemodynamics impact the mechanotransduction in endothelial cells (ECs) lining the vascular network. On the other hand, cancer cells are shown to influence the local hemodynamics in their vicinity, in microvasculature. The first objective of present study is to explore how cancer cell-induced changes in local hemodynamics can impact the forces experienced by intra/inter-cellular organelles of ECs that are believed to play important roles in mechanotransduction. Moreover, extracellular matrix (ECM) stiffening has been shown to correlate with progression of most cancer types. However, it is still not well understood how ECM stiffness impacts ECs mechanosensors. The second objective of this study is to elucidate the role of ECM stiffness on mechanotransduction in ECs. Methods-A three-dimensional, multiscale, multicomponent, viscoelastic model of focally adhered ECs is developed to simulate the force transmission through ECs mechanosensors [actin cortical layer, nucleus, cytoskeleton, focal adhesions (FAs), and adherens junctions (ADJs)]. Results-Our results show that cancer cell-altered hemodynamics results in significantly high forces transmitted to subcellular organelles of ECs which are in vicinity of cancer cells. This impact is more drastic on stress fibers (SFs) both centrally located and peripheral ones. Furthermore, we demonstrate that ADJs, FAs, and SFs experience higher stresses in ECs attached to stiffer ECM. Impact of ECM stiffness is particularly significant in ECs exposed to fluid shear stresses of 2 Pa or lower. This finding reveals the role of organ-specific stiffness in promoting cancer cell transmigration even in capillaries larger than cancer cell diameter. Conclusions-ÊCancer cell-induced-changes in ECs mechanotransduction represents an important potential mechanism for cancer cell transmigration in the microvasculature particularly with stiffer ECM. The identification of ECs mechanosensors involved in early stages of EC-cancer cell interaction will help with developing more efficient therapeutic interventions to suppress cancer cell transmigration in the microvasculature.