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.

Keywords: cancer stem cells; drug resistance; reactive oxygen species; tumour microenvironmental stress.

Figure 1

External stressors promote and drive a cancer-prone environment via the generation of oxidative stress in a tumour microenvironment (TME). Acute and chronic stressors generate oxidative stress in the form of ROS within the TME, which affects the composition of the tumour-associated stroma. In turn, the stress-induced tumour-associated stroma promotes cancer cell survival, growth and proliferation, impaired cell differentiation, glucose metabolism and post-translational modifications of cancer-related proteins.

Figure 2

The tumour microenvironment (TME) promotes cancer progression to a multi-drug resistant (MDR) phenotype. The major components of TME, i.e., cancer-associated fibroblasts, reactive oxygen species (ROS), hypoxia, and nutrient deprivation, drive tumours to an adaptive growth, survival and metastatic phenotype that is often attributed to cancer stem cells.

Figure 3

Targeting tumour microenvironment (TME) as a future strategy to overcome multi-drug resistance. In response to specific targeted therapies and standard chemotherapeutics, external and internal stress within the TME drives and promotes cancer adaptation in the form of drug resistance and metastasis. Targeting the ROS-TME circuit interrupts the TME-to-tumour communication that maintains a multi-drug resistance phenotype. This future strategy to target TME has the potential to disrupt the cancer adaption response, which could re-instate the efficacy of specific targeted therapies and standard chemotherapeutics in an attempt to treat cancer successfully.