Abstract：Hypoxia is the most common tumor microenvironment caused by rapid proliferation of tumor cells, and hypoxia-inducible factor (HIF) is the main transcription factor for tumor cells to adapt to hypoxia. Current research has found that HIF can interact with a variety of mesenchymal cells such as fibroblasts, endothelial cells and immune cells in the tumor microenvironment, leading to the transcription and expression of target genes in response to hypoxia, which ultimately promotes tumor angiogenesis, and induces physiological changes such as migration, invasion, and immune escape of tumor cells. However, the signaling pathways involved in the HIF regulatory mechanism are complex, and the mechanism of HIF in the tumor microenvironment need to be further investigated, also most HIF inhibitors are still in the preclinical research stage. This paper reviews the research progress on the effects of HIF on tumor mesenchymal stromal cells to provide a theoretical basis for the diagnosis, prevention and treatment of tumors targeting HIF.
[1] SEMENZA G L,ROTH P H,FANG H M,et al.Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1[J].J Biol Chem,1994,269(38):23757-23763. [2] CHEN P Z,DUAN X H,LI X G,et al.HIPK2 suppresses tumor growth and progression of hepatocellular carcinoma through promoting the degradation of HIF-1α[J].Oncogene,2020,39(14):2863-2876. [3] HOEFFLIN R,HARLANDER S,SCHAFER S,et al.HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice[J].Nat Commun,2020,11(1):1-21. [4] YUAN Y Y,LI H M,PU W,et al.Cancer metabolism and tumor microenvironment:fostering each other?[J].Sci China Life Sci,2022,65(2):236-279. [5] CHU Q F,GU X Y,ZHENG Q X,et al.Regulatory mechanism of HIF-1α and its role in liver diseases:a narrative review[J].Ann Transl Med,2022,10(2):1-15. [6] YAZDANI B,SIROUS H.Expression analysis of HIF-3α as a potent prognostic biomarker in various types of human cancers:a case of meta-analysis[J].Res Pharm Sci,2022,17(5):508-526. [7] DE HEER E C,JALVING M,HARRIS A L.HIFs,angiogenesis,and metabolism:elusive enemies in breast cancer[J].J Clin Invest,2020,130(10):5074-5087. [8] COWMAN S J,KOH M Y.Revisiting the HIF switch in the tumor and its immune microenvironment[J].Trends Cancer,2022,8(1):28-42. [9] SAHAI E,ASTSATUROV I,CUKIERMAN E,et al.A framework for advancing our understanding of cancer-associated fibroblasts[J].Nat Rev Cancer,2020,20(3):174-186. [10] JIN Y,BIAN S,WANG H,et al.CRMP2 derived from cancer associated fibroblasts facilitates progression of ovarian cancer via HIF-1α-glycolysis signaling pathway[J/OL].Cell Death Dis,2022[2023-12-04].https://doi.org/10.1038/s41419-022-05129-5. [11] YANG Y F,GU J Y,LI X,et al.HIF-1α promotes the migration and invasion of cancer-associated fibroblasts by miR-210[J].Aging Dis,2021,12(7):1794-1807. [12] XU H X,ZHAO J,LI J P,et al.Cancer associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis[J].Cell Death Dis,2022,13(5):1-13. [13] BECKER L M,O'CONNELL J T,VO A P,et al.Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer[J/OL].Cell Rep,2020,31(9)[2023-12-04].https://doi.org/10.1016/j.celrep.2020.107701. [14] MARTIN J D,SEANO G,JAIN R K.Normalizing function of tumor vessels:progress,opportunities,and challenges[J].Annu Rev Physiol,2019,81:505-534. [15] VIMALRAJ S.A concise review of VEGF,PDGF,FGF,Notch,angiopoietin,and HGF signalling in tumor angiogenesis with a focus on alternative approaches and future directions[J].Int J Biol Macromol,2022,221:1428-1438. [16] YU X Y,WANG Y,QIU H L,et al.AEG-1 contributes to metastasis in hypoxia-related ovarian cancer by modulating the HIF-1α/NF-κB/VEGF pathway[J/OL].Biomed Res Int,2018,2018[2023-12-04].https://doi.org/10.1155/2018/3145689. [17] TSAI H L,MIAO Z F,CHEN Y T,et al.miR-148a inhibits early relapsed colorectal cancers and the secretion of VEGF by indirectly targeting HIF-1α under non-hypoxia/hypoxia conditions[J].J Cell Mol Med,2019,23(5):3572-3582. [18] RAY U,ROY C S,VASUDEVAN M,et al.Gene regulatory networking reveals the molecular cue to lysophosphatidic acid-induced metabolic adaptations in ovarian cancer cells[J].Mol Oncol,2017,11(5):491-516. [19] YAN Y Y,LIU F X,HAN L,et al.HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways[J/OL].J Exp Clin Cancer Res,2018,37(1)[2023-12-04].https://doi.org/10.1186/s13046-018-0925-x. [20] JANASZAK-JASIECKA A,SIEKIERZYCKA A,PLOSKA A,et al.Endothelial dysfunction driven by hypoxia—the influence of oxygen deficiency on NO bioavailability[J].Biomolecules,2021,11(7):1-21. [21] ZHANG J Y,ZHANG Q,LOU Y,et al.Hypoxia-inducible factor-1α/interleukin-1β signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment[J].Hepatology,2018,67(5):1872-1889. [22] CHEN F,CHEN J N,YANG L B,et al.Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells[J].Nat Cell Biol,2019,21(4):498-510. [23] WU J Y,HUANG T W,HSIEH Y T,et al.Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor[J].Mol Cell,2020,77(2):213-227. [24] LIU N,LUO J,KUANG D,et al.Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression[J].J Clin Invest,2019,129(2):631-646. [25] ZHOU Z G,LIU Y,SONG W,et al.Metabolic reprogramming mediated PD-L1 depression and hypoxia reversion to reactivate tumor therapy[J].J Control Release,2022,352:793-812. [26] CHIU D K C,TSE A P W,XU I M J,et al.Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma[J].Nat Commun,2017,8(1):1-12. [27] LI J Y,WANG L P,CHEN X F,et al.CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer[J].Oncoimmunology,2017,6(6):1-13. [28] ZHANG Z Y,ZHENG Y J,CHEN Y,et al.Gut fungi enhances immunosuppressive function of myeloid-derived suppressor cells by activating PKM2-dependent glycolysis to promote colorectal tumorigenesis[J/OL].Exp Hematol Oncol,2022,11(1)[2023-12-04].https://doi.org/10.1186/s40164-022-00334-6. [29] LIU B C,WEI C Y.Hypoxia induces overexpression of CCL28 to recruit Treg cells to enhance angiogenesis in lung adenocarcinoma[J].J Environ Pathol Toxicol Oncol,2021,40(1):65-74. [30] HSIAO H W,HSU T S,LIU W H,et al.Deltex1 antagonizes HIF-1α and sustains the stability of regulatory T cells in vivo[J/OL].Nat Commun,2015,6[2023-12-04].https://doi.org/10.1038/ncomms7353. [31] HSU T S,LIN Y L,WANG Y A,et al.HIF-2α is indispensable for regulatory T cell function[J].Nat Commun,2020,11(1):1-16. [32] LIIKANEN I,LAUHAN C,QUON S,et al.Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+T cells[J].J Clin Invest,2021,131(7):1-18. [33] PANG L,NG K T P,LIU J,et al.Plasmacytoid dendritic cells recruited by HIF-1α/eADO/ADORA1 signaling induce immunosuppression in hepatocellular carcinoma[J].Cancer Lett,2021,522:80-92. [34] LIU J,ZHANG X M,CHEN K,et al.CCR7 Chemokine receptor-inducible lnc-Dpf3 restrains dendritic cell migration by inhibiting HIF-1α-mediated glycolysis[J].Immunity,2019,50(3):600-615. [35] SHIRAVAND Y,KHODADADI F,KASHANI S,et al.Immune checkpoint inhibitors in cancer therapy[J].Curr Oncol,2022,29(5):3044-3060. [36] KIM B S,LEE K,JUNG H J,et al.HIF-1alpha suppressing small molecule,LW6,inhibits cancer cell growth by binding to calcineurin b homologous protein 1[J].Biochem Biophys Res Commun,2015,458(1):14-20. [37] BAILEY C M,LIU Y,LIU M Y,et al.Targeting HIF-1α abrogates PD-L1-mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues[J].J Clin Invest,2022,132(9):1-14. [38] SENAVIRATHNA L K,HUANG C Q,YANG X Y,et al.Hypoxia induces pulmonary fibroblast proliferation through NFAT signaling[J].Sci Rep,2018,8(1):1-16. [39] JONASCH E,DONSKOV F,ILIOPOULOS O,et al.Belzutifan for renal cell carcinoma in von Hippel-Lindau Disease[J].N Engl J Med,2021,385(22):2036-2046.
