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Review
. 2020 Jan;146(1):19-31.
doi: 10.1007/s00432-019-03080-1. Epub 2019 Nov 16.

Hypoxia in solid tumors: a key promoter of cancer stem cell (CSC) resistance

Masoud Najafi  1 , Bagher Farhood  2 , Keywan Mortezaee  3   4 , Ebrahim Kharazinejad  5 , Jamal Majidpoor  6 , Reza Ahadi  6
Affiliations
Review

Hypoxia in solid tumors: a key promoter of cancer stem cell (CSC) resistance

Masoud Najafi et al. J Cancer Res Clin Oncol. 2020 Jan.

Abstract

Purpose: Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy.

Results: Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior.

Conclusion: Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.

Keywords: Adaptation; Cancer stem cell (CSC); Hypoxia; Hypoxia-inducible factor (HIF); Resistance; Stemness; Tumor microenvironment (TME).

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Conflict of interest statement

The author(s) declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Types of hypoxia. Hypoxia is classified into acute and chronic phases, with either one exhibiting diverse roles in cancer stem cell (CSC) resistance. HIF hypoxia-inducible factor
Fig. 2
Fig. 2
Hypoxia-inducible effects on cellular plasticity. The diagram unveils different characteristics of cells seeded in various areas of tumor (core/edge) or in the metastatic site, causing an adaptive system developed per time. Hypoxia would take a critical role for development of this adaptation. Cancer stem cells (CSCs) residing in the core are proliferative due to exposure to acute hypoxia, while exposure to high range of hypoxia in the edge can cause cellular quiescence and resistance. CSC resistance is maintained in the edge by intense interactions with tumor microenvironment (TME) immune cells, including regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressive cells (MDSCs). The activity of cancer-associated fibroblasts (CAFs) is also high in this area forming a supportive niche for maintaining quiescent (dormant) state in CSCs, thus guiding cellular invasion. Chronically hypoxic edge area promotes a transition in tumor suppressor cytotoxic T lymphocytes (CTLs) from the edge to core. Thus, the core area is immunologically hot, while the edge is immunologically cold. Early colonized cells first remain dormant so as to develop mechanisms of adaptation, and then the adapted cells initiate proliferation by shifting their phenotype from epithelial–mesenchymal transition (EMT) into mesenchymal–epithelial transition (MET). The cells would finally change their phenotype into EMT, which is for multi-organ dispersing
Fig. 3
Fig. 3
Responses from cancer stem cells (CSCs) to oxygen. a CSCs are equipped with a highly qualified redox balance system. An increase in the rate of reactive oxygen species (ROS) causes a shift in the metabolic demand toward glycolysis through induction of hypoxia-inducible factor (HIF)-1α. Glycolysis would then reduce the accelerated ROS levels by glutathione (GSH) induction. b CSCs have different responses to varied concentrations of oxygen. CSCs acquire epithelial–mesenchymal transition (EMT) and invasion upon exposure to both low and moderate oxygen levels, while very low or very high oxygen concentrations could cause CSC death. DDR, DNA damage response
Fig. 4
Fig. 4
Diagram summarizing roles for hypoxia in mediating cancer stem cell (CSC) resistance to hypoxia. CSCs exploit diverse mechanisms under hypoxia in order to adapt and evade the environmental barriers. ECM, extracellular matrix; EC, endothelial cell; TME, tumor microenvironment; EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition; and PI3K, phosphoinositide 3-kinase
See this image and copyright information in PMC

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