Strategies Of Mechanical Adaptation Of Ctcs To Blood Circulation

Although metastatic spread is the lead cause of cancer related mortality and morbidity, its mechanism is still poorly understood. It is accepted that cancer cells are released by primary tumors into blood where they form circulating tumor cells (CTCs). They travel with blood and finally some of them extravasate and seed metastatic sites. Since majority of CTCs during intravasation represent epithelial phenotype, they are poorly equipped to survive shear forces encountered in circulation. Therefore, to be the successful seeds, CTCs have to adapt their mechanical properties by rebuilding their cytoskeleton and turning on selected molecular pathways. We noted that in prostate cancer patients, CTCs isolated from blood show adaptations that increase their invasiveness. Some CTCs form clusters that often include other types of blood cells. This way CTCs avoid death by immune attract or anoikis. Other CTCs turn on a program of epithelial to mesenchymal transition (EMT) that supports free travel with a caveat of easy cell destruction. Finally, some CTCs become stiff that can take safely a long journey. We used atomic force microscopy (AFM) to assess forces that control association between model CTCs leading to formation of clusters. We noted that capabilities of these cells to bond together are connected to their invasiveness and to certain extend are controlled by their EMT status. Using a model of blood circulation system we found that CTCs respond to fluid shear stress (FSS) with induction of EMT and clusters formation. AFM imaging detected that such cells become more adhesive but their elasticity tends to split into two groups of very soft or stiff cells. We conclude that the mechanical adaptations of CTCs may help to better understand mechanisms beyond the metastasis spread and may lead to design new therapies disrupting their invasiveness.