Integration of mechanical and ECM microenvironment signals in the determination of cancer stem cell states

Abstract

Purpose of review: Cancer stem cells (CSCs) are increasingly understood to play a central role in tumor progression. Growing evidence implicates tumor microenvironments as a source of signals that regulate or even impose CSC states on tumor cells. This review explores points of integration for microenvironment-derived signals that are thought to regulate CSCs in carcinomas.

Recent findings: CSC states are directly regulated by the mechanical properties and extra cellular matrix (ECM) composition of tumor microenvironments that promote CSC growth and survival, which may explain some modes of therapeutic resistance. CSCs sense mechanical forces and ECM composition through integrins and other cell surface receptors, which then activate a number of intracellular signaling pathways. The relevant signaling events are dynamic and context-dependent.

Summary: CSCs are thought to drive cancer metastases and therapeutic resistance. Cells that are in CSC states and more differentiated states appear to be reversible and conditional upon the components of the tumor microenvironment. Signals imposed by tumor microenvironment are of a combinatorial nature, ultimately representing the integration of multiple physical and chemical signals. Comprehensive understanding of the tumor microenvironment-imposed signaling that maintains cells in CSC states may guide future therapeutic interventions.

Keywords: Cancer stem cell; extracellular matrix; mechano-signaling; signaling integration; tumor microenvironment.

Figure 1.. Integration of mechanical- and ECM-based tumor microenvironment-imposed signals.

Cancer stem cells sense mechanical forces and ECM to activate intracellular signaling through the indicated cell surface receptors. FAK, ILK, RhoA and hippo pathway (YAP/TAZ) are points of integration for these different types of signals that regulate CSC states.