The hypoxic microenvironment: A determinant of cancer stem cell evolution

Abstract

Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and is a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior.

Downregulation of mitochondrial cyclooxygenase-2 inhibits the stemness of nasopharyngeal carcinoma by decreasing the activity of dynamin-related-protein 1

“…COX-2 in the tumor microenvironment was critical for the induction and maintenance of cancer stemness 53. It is known a hypoxic microenvironment and hypoxia-inducible factor-1α (HIF-1α) perform a critical role in maintaining the stemness of CSCs 54, 55. Csiki et al reported that HIF-1α activated the transcription of COX-2 by interaction with the PTGS2 promoter in non-small cell lung cancer cell 56.…”

Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells

“…HIF-1α induced by hypoxia has been found to promote upregulation of Snail and to attenuate the expression of E-cadherin, leading to EMT and increased cancer aggressiveness [21]. Hypoxia and induction of HIF-1α have also been shown to expand the subpopulation of cancer stem-like cells and to increase resistance to therapies in various cancer types [22,23,24]. Although a direct involvement of increased expression of HIF-1α under hypoxia is understandable, we have observed a relatively high basal level of HIF-1α in one of the analyzed HNSCC cell lines.…”

Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

“…It is thought that through self-renewal and differentiation, cancer stem cells are responsible for the production of the various tumor cell types and contribute to tumor heterogeneity. Furthermore, according to this hypothesis, tumor metastases and resistance to therapies arise directly from cancer stem cells [25]. Cancer-initiating stem cells have been isolated in leukaemia and in solid tumors such as breast, lung and gynecologycal malignancies [26].…”