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

Brittany Durden,Vineet K. Gupta,Vanessa Garrido,Shweta P. Lavania,Sulagna Banerjee,Beatriz Mateo-Victoriano,Kousik Kesh

doi:10.3390/cancers12103067

Brittany Durden, Vineet K. Gupta + Show 5 more

Open Access

https://doi.org/10.3390/cancers12103067

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Abstract

Simple SummaryThe 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.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.

Highlights

The extracellular matrix (ECM) has long been considered as the inactive and physical component of any tissue
We focus on how the ECM provides a favorable niche for the enrichment of cancer stem cells (CSCs) and modulates the immune microenvironment and whether it can be targeted to sensitize pancreatic tumors to chemoand immune therapy
Hypoxia is an important feature of the CSC niche, especially in solid malignancies, wherein, apart from the glucose-based metabolism, the hypoxic environment may favor the transformation of cancer cells towards a stem-like phenotype which allows them to utilize several sources of energy

Summary

Introduction

The extracellular matrix (ECM) has long been considered as the inactive and physical component of any tissue. The ECM components like collagen and hyaluronan form a significant part of the tumor They exert pressure on the blood vessels, constricting them and functionally impairing them, thereby creating a physical barrier which prevents effective drug delivery, thereby contributing to therapy resistance [2,3,4]. It is not clear whether the ECM components affect intra-tumoral and microenvironmental factors that lead to chemo- and immune resistance. One of the key contributors to therapy resistance is the treatment-refractory population of cancer stem cells (CSCs) within the tumors that are selected and enriched upon interaction with the microenvironment [5,6]. We will review how the cellular and the acellular components of the niche select for the CSC population within a tumor and govern its function

Enrichment of CSC Population within the Tumor

ECM and Stem Cell Homeostasis

ECM–Integrin Interaction and Stemness

Role of Collagen in CSC Enrichment and Function

Proteoglycans and CSC

Hyaluronan and CSCs

Hypoxia in Regulation of ECM and CSC Metabolism

ECM Regulated-Metastasis in CSCs

Cancer Stem Cell-Derived ECM Maintains Immune Evasion

Targeting Extracellular Matrix to Remodel CSC Niche

Conclusions