• The Role of Cancer Stem Cells in Chemoresistance
  • Behnaz Mansoori ,1 Solmaz Shirjang ,2 Sadegh Babashah,3,*
    1. Tarbiat Modarres University, Tehran, Iran
    2. Immunology Research Center
    3. Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, tehran, iran


  • Introduction: The combination of surgery with chemotherapy or radiotherapy has the best outcome in the treatment of many cancer types. Chemotherapeutic agents have the complex mechanism in their action and could help to activate different death pathways including necrosis, apoptosis, autophagy and other biological pathways. However, after using these agents the high toxicity, recurrence and drug resistance have been considered. Understanding the mechanism of chemoresistance could bring the most beneficial information for predicting the progression and development of novel therapies. In recent years, cancer stem cells (CSCs) have been considered as an essential factor in recurrence and chemoresistance in various types of cancers. The presence of CSCs in tumor environment explain by two theories are included stochastic and hierarchical models. In the stochastic model, cancer cells can differentiate into CSCs and in hierarchical model CSCs are the progenitor of differentiated cancer cells. Due to the low proliferation rate and quiescence of CSCs, they could escape from cytotoxic effect of chemotherapy drugs and consequently drug-resistant occurred. These cells are also capable of self-renewal and can generate mature differentiated cancer cells with genomic alterations. Following this, the reducing susceptibility of tumor cells against chemotherapeutic agents occurs. Generally, two internal and external factors are associated with the role of CSCs in chemoresistance. Internal factors are including 1) Increased DNA repair. The increasing of DNA repair in the tumor can overcome chemotherapy drugs-induced DNA damages and consequently reduced apoptotic cell death. 2) Increased expression of ATP-binding cassette (ABC) family. ABC proteins are membrane transporters that can pump drugs out of the cells and lead to the desensitization of CSCs and cancer cells against chemotherapy drugs. 3) Metabolic state. CSCs possess a variable metabolic state within various types of tumor microenvironments depending on oxygen tension, genetic alteration and different signaling contexts and oncogenic mutations within cancer cells. CD44, as a stemness marker of CSCs, is crucial for the regulation of glycolytic metabolism. External factors are including Cancer microenvironment; Hypoxia leads the induction of hypoxia-inducible factor (HIF‑1α) and HIF‑2α via CSCs. HIF‑1α and HIF‑2α may contribute to the regulation of CSCs maintenance and adaption in hypoxia condition and cause chemoresistance. HIF activity in regions of intratumoral hypoxia mediates epithelial-mesenchymal transition, stem-cell maintenance, and resistance to chemotherapy. Several evidences showed that the targeting of CSCs either their stemness pathways, surface receptors, metabolic pathways, and enzymes can reverse the chemoresistance and bring the beneficial outcome in cancer patients. For achieving the best results we can target the specific tumor markers in combination with the targeting of CSC surface markers such as CD44, CD133, aldehyde dehydrogenases (ALDH) and pathways such as Wnt through CAR-T cell therapy. Although along with them inhibit glycolysis metabolism, glucose transporter and glycolytic enzymes such as GLUT1-4, Hexokinase1-2, Pyruvate kinase M2, lactate dehydrogenase and HIF1-2α can be potential targets for reducing the number of CSCs. Finding the best combination therapy to achieve the best results should be elucidated.
  • Methods: Different databases including Pubmed, ScienceDirect, Google Scholar and Wiley were searched to find the title of the manuscript. Following that we studied 100 different research articles, descriptive and systematic reviews from 2012 to 2019 years and summarized them in a unique introduction form.
  • Results: Several evidences showed that the targeting of CSCs either their stemness pathways, surface receptors, metabolic pathways, and enzymes can reverse the chemoresistance and bring the beneficial outcome in cancer patients. In generally reducing the number and proliferation of CSCs could prolong the survival of cancer patients.
  • Conclusion: For achieving the best outcome we can target the specific tumor markers in combination with the targeting of CSC surface markers such as CD44, CD133, aldehyde dehydrogenases (ALDH) through CAR-T cell therapy. Although along with them the inhibition of glycolysis metabolism, glucose transporter and glycolytic enzymes such as GLUT1-4, Hexokinase1-2, Pyruvate kinase M2, lactate dehydrogenase and HIF1-2α can be potential targets for reducing the number of CSCs. Finding the best combination therapy to achieve the best results should be elucidated.
  • Keywords: Cancer stem cells (CSCs); Chemoresistance; Tumor Microenvironment; Immunotherapy