Integration of Mechanical and ECM Microenvironment Signals in the Determination of Cancer Stem Cell States
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CLASSICAL SIGNALING PATHWAYS (A CARDOSO AND N CARLESSO, SECTION EDITORS)
Integration of Mechanical and ECM Microenvironment Signals in the Determination of Cancer Stem Cell States Tiina A. Jokela 1 & Mark A. LaBarge 1
# Springer Nature Switzerland AG 2020
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 extracellular 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 contextdependent. 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 . Tumor microenvironment . Mechano-signaling . Extracellular matrix . Signaling integration
Introduction Cancer stem cells (CSCs) are thought to be a subpopulation of tumor cells that have the capacity to self-maintain and give rise to the other cells that comprise the bulk of the tumor. CSCs are central players in therapeutic resistance, and they are imbued with the potential to spread and initiate growth in distant locations. CSCs have been identified in many cancers, but it is not clear if all cancer types have CSCs. Part of the confusion surrounding CSCs is a lack of consistency in the This article is part of the Topical Collection on Classical Signalling Pathways * Mark A. LaBarge [email protected] Tiina A. Jokela [email protected] 1
Department of Population Sciences, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA
markers used to enrich for them, for even within one type of cancer there is little consensus as to the identity of the entity. An explanation of this could be that CSCs and more differentiated cancer cells represent transition states and that any cancer cell can occupy those states given the correct set of equilibrium conditions [reviewed in [1]]. Thus, CSCs may be better conceptualized as a functional state rather than as definable entities. Tissue-specific stem cells are maintained in specialized microenviron
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