Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

SIMPLE SUMMARY: The extracellular matrix (ECM) has emerged as a critical part of the tumor microenvironment. This glycoprotein- and proteoglycan-rich part of the tumor serves as a niche for the enrichment of cancer stem cells that can drive resistance to therapy and metastasis. Additionally, the ECM can act as a barrier to drug delivery, thereby physically contributing to resistance to therapy. This review summarizes the role of the ECM in enriching for cancer stem cells and how it contributes to therapy resistance in cancer. Finally, it discusses the attempts to develop molecules that can target the ECM as potential therapy options. ABSTRACT: The extracellular matrix (ECM) has remained an enigmatic component of the tumor microenvironment. It drives metastasis via its interaction with the integrin signaling pathway, contributes to tumor progression and confers therapy resistance by providing a physical barrier around the tumor. The complexity of the ECM lies in its heterogeneous composition and complex glycosylation that can provide a support matrix as well as trigger oncogenic signaling pathways by interacting with the tumor cells. In this review, we attempt to dissect the role of the ECM in enriching for the treatment refractory cancer stem cell population and how it may be involved in regulating their metabolic needs. Additionally, we discuss how the ECM is instrumental in remodeling the tumor immune microenvironment and the potential ways to target this component in order to develop a viable therapy.