Section 3.3.2: The hypoxia microenvironment and CSCs (from DOI: 10.1038/s41392-020-0110-5)
From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5
Section 3.3.2: The hypoxia microenvironment and CSCs
Hypoxia is a key component for CSC formation and maintenance. The hypoxic microenvironment maintains the undifferentiated state of cancer cells, enhances their cloning rate, and induces the expression of CD133 as a specific biomarker of CSCs. HIFs are important transcription factors that regulate cellular hypoxia responsiveness and inhibit cell apoptosis. As a heterodimer, HIF is composed of HIFalpha and HIFbeta. HIF-1alpha regulates the proliferation and fate of CSCs in medulloblastoma and glioblastoma multiforme and activates the NF-kappaB pathway to promote CSC survival and tumorigenesis. HIF-2alpha maintains the survival and phenotype of CSCs. HIFalpha also regulates the expression of the target genes GLUT1, GLUT3, LDHA, and PDK1. Thus, CSCs can adapt to a new method of cell energy metabolism and avoid apoptosis caused by hypoxia.
HIFs also regulate the stemness of CSCs. Previous studies have shown that CSCs need to activate HIF-1alpha and HIF-2alpha to maintain their self-sustainability under hypoxic conditions and obtain pluripotency by upregulating the Sox2 and Oct4 genes. More importantly, activation of C-MYC by HIF-2alpha is necessary to ensure undifferentiated CSCs. The Wnt and Notch signaling pathways regulated by hypoxia and can induce the EMT, which promotes the stemness of CSCs and increases the invasiveness and resistance to radiotherapy and chemotherapy. HIF-1alpha binds the Notch ICD and enhances its transcriptional activity. In the hypoxic microenvironment of glioma, both HIF-1alpha and HIF-2alpha require the Notch signaling pathway to ensure the self-renewal and undifferentiated status of CSCs.
