Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

Autoren

Nuray Erin
Jelena Grahovac
Anamaria Brozovic
Thomas Efferth

DOI

10.1016/j.drup.2020.100715

ISSN

1368-7646

Zeitschrift

Drug Resistance Updates

Sprache

en

Artikelnummer

100715

Paginierung

100715 - 100715

Datum der Veröffentlichung

2020

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.drup.2020.100715

Datum der Datenerfassung

2022

Titel

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

Ausgabe der Zeitschrift

53

Data source: Crossref

Abstract

It is well established that multifactorial drug resistance hinders successful cancer treatment. Tumor cell interactions with the tumor microenvironment (TME) are crucial in epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). TME-induced factors secreted by cancer cells and cancer-associated fibroblasts (CAFs) create an inflammatory microenvironment by recruiting immune cells. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) and inflammatory tumor associated macrophages (TAMs) are main immune cell types which further enhance chronic inflammation. Chronic inflammation nurtures tumor-initiating/cancer stem-like cells (CSCs), induces both EMT and MDR leading to tumor relapses. Pro-thrombotic microenvironment created by inflammatory cytokines and chemokines from TAMs, MDSCs and CAFs is also involved in EMT and MDR. MDSCs are the most common mediators of immunosuppression and are also involved in resistance to targeted therapies, e.g. BRAF inhibitors and oncolytic viruses-based therapies. Expansion of both cancer and stroma cells causes hypoxia by hypoxia-inducible transcription factors (e.g. HIF-1α) resulting in drug resistance. TME factors induce the expression of transcriptional EMT factors, MDR and metabolic adaptation of cancer cells. Promoters of several ATP-binding cassette (ABC) transporter genes contain binding sites for canonical EMT transcription factors, e.g. ZEB, TWIST and SNAIL. Changes in glycolysis, oxidative phosphorylation and autophagy during EMT also promote MDR. Conclusively, EMT signaling simultaneously increases MDR. Owing to the multifactorial nature of MDR, targeting one mechanism seems to be non-sufficient to overcome resistance. Targeting inflammatory processes by immune modulatory compounds such as mTOR inhibitors, demethylating agents, low-dosed histone deacetylase inhibitors may decrease MDR. Targeting EMT and metabolic adaptation by small molecular inhibitors might also reverse MDR. In this review, we summarize evidence for TME components as causative factors of EMT and anticancer drug resistance.

Addresses

Department of Medical Pharmacology, Immunopharmacology and Immunooncology Unit, School of Medicine, Akdeniz University, Turkey. Electronic address: nerin@akdeniz.edu.tr.

Autoren

Nuray Erin
Jelena Grahovac
Anamaria Brozovic
Thomas Efferth

DOI

10.1016/j.drup.2020.100715

eISSN

1532-2084

Externe Identifier

PubMed Identifier: 32679188

Funding acknowledgements

Germany Science Foundation:
TUBITAK: 118S378
Serbian Ministry of Education, Science and Technological Development: 451-03-68/2020-14/200043
Croatian Science Foundation:
German Academic Exchange Service:
German Cancer Aid, the Chinese Scholarship Council:

Open access

false

ISSN

1368-7646

Zeitschrift

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

Schlüsselwörter

Cell Line, Tumor
Animals
Humans
Neoplasms
Disease Models, Animal
Inflammation Mediators
Antineoplastic Combined Chemotherapy Protocols
Drug Resistance, Multiple
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Hypoxia-Inducible Factor 1, alpha Subunit
Histone Deacetylase Inhibitors
TOR Serine-Threonine Kinases
Epithelial-Mesenchymal Transition
Tumor Microenvironment
Cancer-Associated Fibroblasts
DNA Demethylation
Tumor-Associated Macrophages

Sprache

eng

Medium

Print-Electronic

Online publication date

2020

Paginierung

100715

Datum der Veröffentlichung

2020

Status

Published

Datum der Datenerfassung

2020

Titel

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance.

Sub types

Research Support, Non-U.S. Gov't
Review
Journal Article

Ausgabe der Zeitschrift

53

Data source: Europe PubMed Central

Abstract

It is well established that multifactorial drug resistance hinders successful cancer treatment. Tumor cell interactions with the tumor microenvironment (TME) are crucial in epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). TME-induced factors secreted by cancer cells and cancer-associated fibroblasts (CAFs) create an inflammatory microenvironment by recruiting immune cells. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) and inflammatory tumor associated macrophages (TAMs) are main immune cell types which further enhance chronic inflammation. Chronic inflammation nurtures tumor-initiating/cancer stem-like cells (CSCs), induces both EMT and MDR leading to tumor relapses. Pro-thrombotic microenvironment created by inflammatory cytokines and chemokines from TAMs, MDSCs and CAFs is also involved in EMT and MDR. MDSCs are the most common mediators of immunosuppression and are also involved in resistance to targeted therapies, e.g. BRAF inhibitors and oncolytic viruses-based therapies. Expansion of both cancer and stroma cells causes hypoxia by hypoxia-inducible transcription factors (e.g. HIF-1α) resulting in drug resistance. TME factors induce the expression of transcriptional EMT factors, MDR and metabolic adaptation of cancer cells. Promoters of several ATP-binding cassette (ABC) transporter genes contain binding sites for canonical EMT transcription factors, e.g. ZEB, TWIST and SNAIL. Changes in glycolysis, oxidative phosphorylation and autophagy during EMT also promote MDR. Conclusively, EMT signaling simultaneously increases MDR. Owing to the multifactorial nature of MDR, targeting one mechanism seems to be non-sufficient to overcome resistance. Targeting inflammatory processes by immune modulatory compounds such as mTOR inhibitors, demethylating agents, low-dosed histone deacetylase inhibitors may decrease MDR. Targeting EMT and metabolic adaptation by small molecular inhibitors might also reverse MDR. In this review, we summarize evidence for TME components as causative factors of EMT and anticancer drug resistance.

Date of acceptance

2020

Autoren

Nuray Erin
Jelena Grahovac
Anamaria Brozovic
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/32679188

DOI

10.1016/j.drup.2020.100715

eISSN

1532-2084

Zeitschrift

Drug Resist Updat

Schlüsselwörter

Chemotherapy
Hypoxia
Inflammation
Microenvironment
Multidrug resistance
Small molecules
Targeted therapy
Animals
Antineoplastic Combined Chemotherapy Protocols
Cancer-Associated Fibroblasts
Cell Line, Tumor
DNA Demethylation
Disease Models, Animal
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition
Gene Expression Regulation, Neoplastic
Histone Deacetylase Inhibitors
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Inflammation Mediators
Neoplasms
TOR Serine-Threonine Kinases
Tumor Microenvironment
Tumor-Associated Macrophages

Sprache

eng

Country

Scotland

Paginierung

100715

PII

S1368-7646(20)30044-3

Datum der Veröffentlichung

2020

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2021

Titel

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance.

Sub types

Journal Article
Research Support, Non-U.S. Gov't
Review

Ausgabe der Zeitschrift

53

Data source: PubMed

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

Tools