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

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ERİN N., Grahovac J., Brozovic A., Efferth T.

DRUG RESISTANCE UPDATES, cilt.53, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Derleme
  • Cilt numarası: 53
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1016/j.drup.2020.100715
  • Dergi Adı: DRUG RESISTANCE UPDATES
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Chemotherapy, Hypoxia, Inflammation, Microenvironment, Multidrug resistance, Small molecules, Targeted therapy, CANCER-ASSOCIATED FIBROBLASTS, CELL LUNG-CANCER, EPIDERMAL-GROWTH-FACTOR, HYPOXIA-INDUCIBLE FACTOR-1-ALPHA, P-GLYCOPROTEIN EXPRESSION, COLONY-STIMULATING FACTOR, HISTONE DEACETYLASE INHIBITORS, MYELOID SUPPRESSOR-CELLS, ANTI-VEGF THERAPY, NF-KAPPA-B
  • Akdeniz Üniversitesi Adresli: Evet

Özet

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-1 alpha) 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.