Fig. 3.

Hypoxia and shear stress regulate dissemination of circulating tumor cells (CTCs). Cancer cells are in interaction with several types of immune cells and experience various biophysical forces both in the primary tumor microenvironment and in the circulation. Primary tumors have normoxic and hypoxic regions with constant interstitial flow, inducing biochemical and biophysical signaling changes in cancer cells. Cancer cells can intravasate as single cells, as a group of cells (homotypic clusters) or together with non-neoplastic cells (heterotypic clusters). When CTCs enter the bloodstream, they are subjected to different levels of fluid shear stress that can lead to cell rupture and apoptosis, and initiate rapid signaling changes. Due to mechanical shielding, CTC clusters are more resistant to shear stress than single cells. In contrast, single cells are more prone to cell membrane blebbing caused by mechanical forces. MDSC, myeloid-derived suppressor cell; CAF, cancer-associated fibroblast; NK, natural killer cell. Illustrations were created with BioRender.