Tumour Microenvironment Stress Promotes the Development of Drug Resistance

Abstract

Multi-drug resistance (MDR) is a leading cause of cancer-related death, and it continues to be a major barrier to cancer treatment. The tumour microenvironment (TME) has proven to play an essential role in not only cancer progression and metastasis, but also the development of resistance to chemotherapy. Despite the significant advances in the efficacy of anti-cancer therapies, the development of drug resistance remains a major impediment to therapeutic success. This review highlights the interplay between various factors within the TME that collectively initiate or propagate MDR. The key TME-mediated mechanisms of MDR regulation that will be discussed herein include (1) altered metabolic processing and the reactive oxygen species (ROS)-hypoxia inducible factor (HIF) axis; (2) changes in stromal cells; (3) increased cancer cell survival via autophagy and failure of apoptosis; (4) altered drug delivery, uptake, or efflux and (5) the induction of a cancer stem cell (CSC) phenotype. The review also discusses thought-provoking ideas that may assist in overcoming the TME-induced MDR. We conclude that stressors from the TME and exposure to chemotherapeutic agents are strongly linked to the development of MDR in cancer cells. Therefore, there remains a vast area for potential research to further elicit the interplay between factors existing both within and outside the TME. Elucidating the mechanisms within this network is essential for developing new therapeutic strategies that are less prone to failure due to the development of resistance in cancer cells.

Cancer Stem Cells and the Tumor Microenvironment: Targeting the Critical Crosstalk through Nanocarrier Systems

“…The corresponding model is also based off four key features: cellular heterogeneity, self-renewal, limited plasticity within tumor hierarchy, and drug resistance [209]. The multi-drug resistance phenomenon that currently plagues all cancer therapy is on account of CSCs, induced by endogenous detoxifying enzyme expression, higher levels of drug efflux, decreased drug response, hypoxic stress on the TME, or even increased DNA repair activity [31, [210][211][212][213]. The mechanism of CSC drug resistance is via stem cell pathways.…”

Exosome-Derived Non-Coding RNAs in the Tumor Microenvironment of Colorectal Cancer: Possible Functions, Mechanisms and Clinical Applications

“…Exosomal ncRNAs are involved not only in cancer progression and metastasis, but also in treatment resistance development ( 119 ). Obviously, one of the challenges in the treatment of tumor processes during chemoradiotherapy is the development of drug resistance.…”

The Resistance of Cancer Cells to Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, is Mediated by the ABCB1 Transporter

“…MDR is a major cause of cancer chemotherapy failure, which can lead to tumor recurrence and the death of cancer patients ( Lage and Dietel, 2000 ). MDR can occur due to 1) the overexpression of certain adenosine triphosphate (ATP)-binding cassette (ABC) transporter proteins ( Robey et al, 2018 ); 2) an increase in the repair of damaged DNA ( Helleday et al, 2008 ); 3) mutations in the target of the anticancer drugs which decrease or abrogate the efficacy of these drugs ( Chandrasekhar et al, 2019 ); 4) an increased tolerance to the stressful tumor microenvironment (TME) ( Erin et al, 2020 ; Seebacher et al, 2021 ); 5) evasion of programmed cell death ( Shahar and Larisch, 2020 ; Neophytou et al, 2021 ); 6) higher levels of reactive oxidative species ( Cui et al, 2018 ); 7) an increase in the biotransformation of the anticancer drugs to less active or inactive metabolites ( Zaal and Berkers, 2018 ); 8) sequestration of drugs by organelles or intracellular molecules that decrease their interaction with their cellular target(s), and 9) specific long noncoding RNAs (lncRNAs) ( Liu et al, 2020 ). Numerous studies have shown that one of the primary mechanisms that mediates MDR in cancer cells is the overexpression of ABCB1 (i.e., P-gp or MDR1), ABCG2 (i.e., BCRP or MXR), and ABCC1 (i.e., MRP1) transporters ( Fletcher et al, 2016 ), which significantly decrease the intracellular levels of certain anticancer drugs by extrusion from cancer cells, thereby decreasing or even abolishing their efficacy ( Wu and Fu, 2018 ).…”