Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer.

Haiyun Zhang,Milo Co,Xiaozhuo Chen,Alexander Steed

doi:10.20517/cdr.2021.32

Abstract

The cancer stem cell (CSC) state and epithelial-mesenchymal transition (EMT) activation are tightly interconnected. Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain low reactive oxygen species levels and stemness, enhanced drug transporters, anti-apoptotic machinery and DNA repair system. Factors present in the tumor microenvironment such as hypoxia and the communication with non-cancer stromal cells also promote cancer cells to enter the EMT/CSC state and display related resistance. ATP, particularly the high levels of intratumoral extracellular ATP functioning through both signaling pathways and ATP internalization, induces and regulates EMT and CSC. The three of them work together to enhance drug resistance. New findings in each of these factors will help us explore deeper into mechanisms of drug resistance and suggest new resistance-associated markers and therapeutic targets.

Highlights

Drug resistance in cancer is a very complicated process with numerous participating components
Our recent studies have shown that extracellular Adenosine 5’-triphosphate (ATP) in tumor microenvironment (TME) is found in concentrations 103 to 104 times higher than eATP found in normal tissues[1,2,3,4,5]
Prostate cancer cells resistant to androgen deprivation (AD) therapy were characterized by elevated FOXC2, the associated epithelialmesenchymal transition (EMT)/cancer stem cells (CSC) phenotype and increased drug resistance, which were related to the activation of p38 MAPK signaling, a key pathway in promoting cell survival and proliferation[133].The study of the mechanism suggested that FOXC2 augmented p38 phosphorylation[133]

Summary

Introduction

Drug resistance in cancer is a very complicated process with numerous participating components. The expression of ABC transporters is under the regulation of multiple signaling pathways associated with CSC phenotypes and EMT activation, contributing to CSC and EMT-related resistance.

Results

Conclusion