Stemness Maintenance at Hypoxic Niches and Therapeutic Opportunities in Targeting Hypoxic Cancer Stem Cells

Research on stemness and multilineage differentiation mechanisms has gained significant value due to the potential therapeutic impact of stem cell-based approaches. Oxygen (O 2 ) is a key factor controlling stem cell phenotype, and the study of mechanisms and signaling activated at lower O 2 tension, such as those under native microenvironments (hypoxia), is an effective strategy to define whether O 2 is essential in preserving naïve stemness potential and modulating their differentiation. Tumors are a mixture of differentially evolved subpopulations of cells, and hypoxia is considered a major feature of the tumor microenvironment. Recent reports link resistance to conventional therapies and the metastatic potential to a stem-like tumor population, termed cancer stem cells (CSCs). Hypoxia is a major feature of the tumor microenvironment and is a potential contributor to the CSC phenotype and its enhanced tumorigenicity. Targeting the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. Restricted oxygen conditions increase the CSC fraction and promote the acquisition of a stem-like state. CSCs are critical for survival, self-renewal, and tumor growth. CSCs may originate from normal stem cells that have undergone genetic mutations or epigenetic changes. Recent discoveries include the de-differentiation of cancer cells to stem-like cells, which express and upregulate induced pluripotent stem cell markers known as Yamanaka factors. Understanding the mechanisms that give rise to these cells could have important implications for the development of new strategies in cancer treatments and therapies.