The concept that macroscopic tumour stiffness arises from changes in the extracellular matrix (ECM) can be imposed from gathered research data. For example, collagen reorganization leads to an abnormally stiff collagen-enriched stroma. Also, measurements of tissue sections carried out by AFM show regions of higher and lower deformability attributed to stiffness of tumour cells and their environment, respectively. The formation of clinically detectable metastatic sites occurs at the end of stochastic events that allow cells located in the primary tumour site to detach, survive during the transition, and grow in the secondary tumour site. How non-numerous passing cancer cells colonize distant sites knowing that metastasis is a highly inefficient process, remains obscure.
Cancer originates from a single genetically mutated cell capable of proliferating in an uncontrolled manner. To form metastasis, the cell first has to detach from the primary tumour site, invade the surrounding extracellular matrix and pass to lymph or blood circulating systems. In the next steps, the cell extravasates and migrates through surrounding tissue to a site where it forms metastasis, i.e. it starts to proliferate again in an uncontrolled manner. Mechanically, cancerous cells pass through distinct, actively interacting environments. The last decade has delivered several technological and methodological realizations demonstrating that physical stimuli generated by the tumour environment affect cell behaviour and properties as profoundly as biochemical signalling. It has been demonstrated that matrix rigidity highly affects tissue homeostasis, manifesting variations in cell morphology, properties, and behaviour. Various healthy cells like fibroblasts or endothelial cells, or even stem cells alter their shape associated with remodelling of the actin cytoskeleton in response to the stiffness of the surrounding environment. We are trying to answer the extent to which ECM mechanical properties guide cancer cells towards a more migratory phenotype.
Our study demonstrated that morphological and mechanical alterations of bladder cancer cells in response to altered microenvironment stiffness are of biphasic nature. Mechanical properties of the cell microenvironment induce threshold-dependent relations. Initially, fast alterations in cellular capability to spread and to deform are followed by slow-rate changes. A switch provided by cellular deformability threshold, in the case of non-malignant cells, triggers the formation of thick actin bundles accompanied by matured focal adhesions. For cancer cells, cell spreading and deformability thresholds switch between the slow and fast changes with the weak reorganization of actin filaments and focal adhesions formation (Lekka et al., 2019).
- M.Lekka, J. Pabijan, B.Orzechowska – Morphological and mechanical stability of bladder cancer cells in response to substrate rigidity – Biochimica et Biophysica Acta – General Subjects 1863 (2019) 1006-1014.