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    • br HIF HIF signaling in cancer cells contributes to tumor

    2023-01-27


    HIF-1α HIF-1α signaling in cancer cells contributes to tumor progression by promoting angiogenesis, invasion, metastasis, and the recruitment of immunosuppressive cells via secreted modulators 36, 37. One example of a HIF-1α immunosuppressive pathway is through increased expression of inducible nitric oxide synthase (iNOS), which can act on myeloid cells to impair immune cell recruitment to tumors [38]. Similarly, HIF-1α activity regulates the chemotactic properties of immune cell-mediated tumor infiltration by increasing vascular endothelial growth factor (VEGF) production by endothelial cells [39]. VEGF binds to its receptor, neuropilin-1, and attracts Tregs to the tumor site, which is a positive regulator of tumor growth and, therefore, is associated with worse survival outcomes. Similar relationships were observed for TGF-β, which is secreted by malignant cells to attract Tregs to GBM and prevent the killing of cancer cells [23]. HIF-1α has been identified as an important driver of the Warburg effect in several tumors, including GBM 40, 41, 42. Hypoxia, a condition of reduced oxygen supply in tissue, is a well-characterized trigger of HIF-1α-dependent signaling. Under normoxic conditions, prolyl hydroxylase domain-containing proteins (PHD) promote the degradation of HIF-1α, while the HIF-1α inhibitor protein (encoded by Hif1an) suppresses its transcriptional activity 42, 43. However, PHD proteins and the HIF-1α inhibitor are inactivated by hypoxia, resulting in HIF-1α stabilization and the induction of HIF-1α dependent cellular responses, such as promoting angiogenesis, regulating immune cell tumor infiltration, and exerting control over Pyr3 and aerobic metabolic processes 37, 43. HIF-1α is frequently upregulated in solid malignances, such as GBM, due to the hypoxic conditions that characterize the tumor microenvironment [41]. HIF-1α is also activated by additional stimuli besides low oxygen tension, such as extracellular ATP 41, 44 or lactate [33]. HIF-1α complexes with HIF-1β (also known as the AHR nuclear translocator, ARNT) to regulate the expression of target genes [45]. The HIF-1α–HIF-1β complex translocates to the nucleus to control the expression of genes that contain hypoxia-response consensus sequences (HREs) in their regulatory regions 40, 46. HIF-1α is an important regulator of the expression of glycolytic enzymes under hypoxic conditions [47]. For example, HIF-1α promotes the expression of hexokinase 2 (HK2), an enzyme upregulated in GBM that has a critical role in the initiation of glycolysis 48, 49. HIF-1α also promotes the expression of the pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase, thereby limiting the entry of pyruvate into the TCA cycle [50]. Thus, HIF-1α increases glycolysis by direct stimulation of key components of this metabolic pathway. Surprisingly, HIF-1α and its close isoform HIF-2α may have opposing activities in cancer depending on the cellular context 51, 52. Moreover, HIF-1α and HIF-2α are relatively ubiquitous in cells, but are regulated differentially. For instance, HIF-1α expression increases under hypoxic conditions, while HIF-2α expression is increased with higher oxygen levels [43]. Production of NO is dependent on the differential expression of HIF-1α and HIF-2α, which are themselves regulated by interferon (IFN)-γ 43, 53, 54. NO production controls immune cell migration to the tumor site and high NO levels, caused by HIF-1α, lead to immunosuppressive functions. However, only HIF-2α is associated with poor prognosis in glioma 55, 56. These effects are thought to be mediated, at least partially, through the inhibition of stem-like features of tumor cells, thereby arresting tumor growth [55]. Additional mechanisms enhance glycolysis in glioma. IDH1, for example, is found to be mutated in 20% of GBM cases, especially in younger patients 57, 58. IDH1 is a critical component of the TCA through the generation of α-ketoglutarate, a metabolite that destabilizes HIF-1α. A unique CpG island methylation pattern was identified in patients with GBM bearing IDH1 mutations [59]. Importantly, the mutant form of IDH1 can inhibit the activity of normal IDH1 in a dominant fashion. Moreover, mutated IDH1 increases the levels of HIF-1α by protecting it from degradation 29, 60, 61. In gliomas that express a mutated form of IDH1 (R132H), HIF-1α transcriptional activity is increased, which leads to worsened glioma outcomes, at least partially through HIF-1α as a result of increased angiogenesis and other HIF-1α-dependent processes that occur in hypoxic environments. Similar effects have been described in association with overexpressed miRNAs that correlate with poor survival in GBM. Indeed, miR-148a and miR-31, which involve HIF-1α signaling, were shown to regulate glioma growth and angiogenesis [62]. Thus, in addition to hypoxia and other metabolic changes associated with the tumor microenvironment, IDH1 mutations and epigenetic changes accompanying GBM activate HIF-1α, reinforcing the metabolic remodeling that promotes tumorigenesis and glioma pathogenesis.