Hypoxia-Induced Phenotypes that Mediate Tumor Heterogeneity

  • Jin Qian
  • Erinn B. RankinEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1136)


Intratumoral heterogeneity is an important factor contributing to metastasis and therapy resistance. The phenotypic diversity of cancer cells within the tumor microenvironment is strongly influenced by microenvironmental factors such as hypoxia. Clinically, hypoxia and the hypoxia inducible transcription factors HIF-1 and HIF-2 are associated with cancer stem cells, metastasis and drug resistance in multiple tumor types. Experimental models have demonstrated an important functional role for HIF signaling in driving CSC, metastatic and drug resistant phenotypes in vitro and in vivo. Here we will review recent studies that highlight novel mechanisms by which hypoxia promotes cancer stem cell, metastatic and drug resistant phenotypes.


Hypoxia Metastasis Stemness Cancer stem cell HIF Therapy resistance Chemotherapy Metabolism 



This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Department of Defense Ovarian Cancer Research Program under Award No. W81XWH-15-1-0097 (EBR). We apologize to those colleagues whose work we could not cite due to space constraints.


  1. 1.
    Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14:611–629. Scholar
  2. 2.
    Brown JM, Giaccia AJ (1998) The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 58:1408–1416PubMedGoogle Scholar
  3. 3.
    Oskarsson T, Batlle E, Massague J (2014) Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14:306–321. Scholar
  4. 4.
    Jaakkola P et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468–472. doi: 1059796 [pii]
  5. 5.
    Rankin EB, Giaccia AJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15: 678–685. doi: cdd200821 [pii] 10.1038/cdd.2008.21Google Scholar
  6. 6.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737CrossRefGoogle Scholar
  7. 7.
    Batlle E, Clevers H (2017) Cancer stem cells revisited. Nat Med 23:1124–1134. Scholar
  8. 8.
    Plaks V, Kong N, Werb Z (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16:225–238. Scholar
  9. 9.
    Oliveira-Costa JP et al (2011) Differential expression of HIF-1alpha in CD44+CD24−/low breast ductal carcinomas. Diagn Pathol 6:73. Scholar
  10. 10.
    Wang Y, Liu Y, Malek SN, Zheng P, Liu Y (2011) Targeting HIF1alpha eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 8:399–411. Scholar
  11. 11.
    Li Z et al (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501–513. Scholar
  12. 12.
    Samanta D, Gilkes DM, Chaturvedi P, Xiang L, Semenza GL (2014) Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci USA 111:E5429–E5438. Scholar
  13. 13.
    Schwab LP et al (2012) Hypoxia-inducible factor 1alpha promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res 14:R6. Scholar
  14. 14.
    Cecil DL et al (2017) Immunization against HIF-1alpha inhibits the growth of basal mammary tumors and targets mammary stem cells in vivo. Clin Cancer Res 23:3396–3404. Scholar
  15. 15.
    Zhang H, Li H, Xi HS, Li S (2012) HIF1alpha is required for survival maintenance of chronic myeloid leukemia stem cells. Blood 119:2595–2607. Scholar
  16. 16.
    Mallard BW, Tiralongo J (2017) Cancer stem cell marker glycosylation: nature, function and significance. Glycoconj J 34:441–452. Scholar
  17. 17.
    Li J et al (2017) Lipid desaturation is a metabolic marker and therapeutic target of ovarian cancer stem cells. Cell Stem Cell 20:303–314 e305. Scholar
  18. 18.
    Glumac PM, LeBeau AM (2018) The role of CD133 in cancer: a concise review. Clin Transl Med 7:18. Scholar
  19. 19.
    Bar EE, Lin A, Mahairaki V, Matsui W, Eberhart CG (2010) Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol 177:1491–1502. Scholar
  20. 20.
    Soeda A et al (2009) Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28:3949–3959. Scholar
  21. 21.
    Iida H, Suzuki M, Goitsuka R, Ueno H (2012) Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2. Int J Oncol 40:71–79. Scholar
  22. 22.
    Ohnishi S et al (2013) Hypoxia-inducible factors activate CD133 promoter through ETS family transcription factors. PLoS One 8:e66255. Scholar
  23. 23.
    Overdevest JB et al (2012) CD24 expression is important in male urothelial tumorigenesis and metastasis in mice and is androgen regulated. Proc Natl Acad Sci USA 109:E3588–E3596. Scholar
  24. 24.
    Lee TK et al (2011) CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 9:50–63. Scholar
  25. 25.
    Thomas S et al (2012) CD24 is an effector of HIF-1-driven primary tumor growth and metastasis. Cancer Res 72:5600–5612. Scholar
  26. 26.
    Pietras A et al (2014) Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell 14:357–369. Scholar
  27. 27.
    Johansson E et al (2017) CD44 interacts with HIF-2alpha to modulate the hypoxic phenotype of perinecrotic and perivascular glioma cells. Cell Rep 20:1641–1653. Scholar
  28. 28.
    Boiani M, Scholer HR (2005) Regulatory networks in embryo-derived pluripotent stem cells. Nat Rev Mol Cell Biol 6:872–884. Scholar
  29. 29.
    Boyer LA et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956. Scholar
  30. 30.
    Ben-Porath I et al (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507. Scholar
  31. 31.
    Hu T et al (2008) Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res 68:6533–6540. Scholar
  32. 32.
    Sarig R et al (2010) Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells. J Exp Med 207:2127–2140. Scholar
  33. 33.
    Hu G et al (2009) A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. Genes Dev 23:837–848. Scholar
  34. 34.
    Ikushima H et al (2009) Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5:504–514. Scholar
  35. 35.
    Jeter CR et al (2009) Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 27:993–1005. Scholar
  36. 36.
    Cowden Dahl KD et al (2005) Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation. Mol Cell Biol 25:10479–10491. Scholar
  37. 37.
    Covello KL et al (2006) HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 20:557–570. Scholar
  38. 38.
    Mathieu J et al (2011) HIF induces human embryonic stem cell markers in cancer cells. Cancer Res 71:4640–4652. Scholar
  39. 39.
    Bae KM, Dai Y, Vieweg J, Siemann DW (2016) Hypoxia regulates SOX2 expression to promote prostate cancer cell invasion and sphere formation. Am J Cancer Res 6:1078–1088PubMedPubMedCentralGoogle Scholar
  40. 40.
    Kumar SM et al (2012) Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene 31:4898–4911. Scholar
  41. 41.
    Seo EJ et al (2016) Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer. Oncotarget 7:55624–55638. Scholar
  42. 42.
    Lan J et al (2018) Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment. Proc Natl Acad Sci USA. Scholar
  43. 43.
    Lu H et al (2015) Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype. Proc Natl Acad Sci USA 112:E4600–E4609. Scholar
  44. 44.
    Zhang C et al (2016) Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA 113:E2047–E2056. Scholar
  45. 45.
    Meyer KD, Jaffrey SR (2014) The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol 15:313–326. Scholar
  46. 46.
    Geula S et al (2015) Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347:1002–1006. Scholar
  47. 47.
    Takebe N et al (2015) Targeting Notch, hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12:445–464. Scholar
  48. 48.
    Keith B, Simon MC (2007) Hypoxia-inducible factors, stem cells, and cancer. Cell 129:465–472. Scholar
  49. 49.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776CrossRefGoogle Scholar
  50. 50.
    Gustafsson MV et al (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9:617–628. Scholar
  51. 51.
    Qiang L et al (2012) HIF-1alpha is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway. Cell Death Differ 19:284–294. Scholar
  52. 52.
    Man J et al (2018) Hypoxic induction of vasorin regulates Notch1 turnover to maintain glioma stem-like cells. Cell Stem Cell 22:104–118 e106. Scholar
  53. 53.
    Dong HJ et al (2016) The wnt/beta-catenin signaling/Id2 cascade mediates the effects of hypoxia on the hierarchy of colorectal-cancer stem cells. Sci Rep 6:22966. Scholar
  54. 54.
    Giambra V et al (2015) Leukemia stem cells in T-ALL require active Hif1alpha and wnt signaling. Blood 125:3917–3927. Scholar
  55. 55.
    Almiron Bonnin DA et al (2018) Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia. Oncogene 37:1107–1118. Scholar
  56. 56.
    Qin J et al (2017) Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression. Sci Rep 7:10592. Scholar
  57. 57.
    Kim H, Lin Q, Glazer PM, Yun Z (2018) The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells. Breast Cancer Res 20:16. Scholar
  58. 58.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:S0092-8674(11)00127-9 [pii] 10.1016/j.cell.2011.02.013Google Scholar
  59. 59.
    Samanta D et al (2016) PHGDH expression is required for mitochondrial redox homeostasis, breast Cancer stem cell maintenance, and lung metastasis. Cancer Res 76:4430–4442. Scholar
  60. 60.
    Luo M et al (2018) Targeting breast Cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab 28:69–86 e66. Scholar
  61. 61.
    Lee KM et al (2017) MYC and MCL1 cooperatively promote chemotherapy-resistant breast Cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab 26:633–647 e637. Scholar
  62. 62.
    Schmidt JM et al (2015) Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep 10:131–139. Scholar
  63. 63.
    Krishnamachary B et al (2006) Hypoxia-inducible factor-1-dependent repression of E-cadherin in von hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res 66:2725–2731. doi:66/5/2725 [pii] 10.1158/0008-5472.CAN-05-3719Google Scholar
  64. 64.
    Yang MH et al (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10: 295–305. doi:ncb1691 [pii] 10.1038/ncb1691Google Scholar
  65. 65.
    Imai T et al (2003) Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol 163: 1437–1447. doi:S0002-9440(10)63501-8 [pii] 10.1016/S0002-9440(10)63501-8Google Scholar
  66. 66.
    Rankin EB, Giaccia AJ (2016) Hypoxic control of metastasis. Science 352:175–180. Scholar
  67. 67.
    Yang SW et al (2017) HIF-1alpha induces the epithelial-mesenchymal transition in gastric cancer stem cells through the Snail pathway. Oncotarget 8:9535–9545. Scholar
  68. 68.
    Tang YA et al (2018) Hypoxic tumor microenvironment activates GLI2 via HIF-1alpha and TGF-beta2 to promote chemoresistance in colorectal cancer. Proc Natl Acad Sci USA 115:E5990–E5999. Scholar
  69. 69.
    Lupia M, Cavallaro U (2017) Ovarian cancer stem cells: still an elusive entity? Mol Cancer 16:64. Scholar
  70. 70.
    Miao ZF et al (2014) Peritoneal milky spots serve as a hypoxic niche and favor gastric cancer stem/progenitor cell peritoneal dissemination through hypoxia-inducible factor 1alpha. Stem Cells 32:3062–3074. Scholar
  71. 71.
    Maccalli C, Rasul KI, Elawad M, Ferrone S (2018) The role of cancer stem cells in the modulation of anti-tumor immune responses. Semin Cancer Biol. Scholar
  72. 72.
    Hasmim M et al (2013) Cutting edge: hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-beta1. J Immunol 191:5802–5806. Scholar
  73. 73.
    Wei J et al (2011) Hypoxia potentiates glioma-mediated immunosuppression. PLoS One 6:e16195. Scholar
  74. 74.
    Chao MP, Weissman IL, Majeti R (2012) The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 24:225–232. Scholar
  75. 75.
    Zhang H et al (2015) HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci USA 112:E6215–E6223. Scholar
  76. 76.
    Samanta D et al (2018) Chemotherapy induces enrichment of CD47(+)/CD73(+)/PDL1(+) immune evasive triple-negative breast cancer cells. Proc Natl Acad Sci USA 115:E1239–E1248. Scholar
  77. 77.
    Schindl M et al (2002) Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 8:1831–1837PubMedGoogle Scholar
  78. 78.
    Yamamoto Y et al (2008) Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res Treat 110:465–475. Scholar
  79. 79.
    Xing F et al (2011) Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30:4075–4086. Scholar
  80. 80.
    Hannigan G, Troussard AA, Dedhar S (2005) Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer 5:51–63. Scholar
  81. 81.
    Pang MF et al (2016) Tissue stiffness and hypoxia modulate the integrin-linked kinase ILK to control breast Cancer stem-like cells. Cancer Res 76:5277–5287. Scholar
  82. 82.
    Chiou SH et al (2017) BLIMP1 induces transient metastatic heterogeneity in pancreatic Cancer. Cancer Discov 7:1184–1199. Scholar
  83. 83.
    Vergis R et al (2008) Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 9:342–351. Scholar
  84. 84.
    Generali D et al (2006) Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res 12:4562–4568. Scholar
  85. 85.
    Koukourakis MI et al (2002) Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 53:1192–1202CrossRefGoogle Scholar
  86. 86.
    Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410. Scholar
  87. 87.
    Yu KD et al (2013) Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer. Clin Cancer Res 19:2723–2733. Scholar
  88. 88.
    Cao Y et al (2013) Tumor cells upregulate normoxic HIF-1alpha in response to doxorubicin. Cancer Res 73:6230–6242. Scholar
  89. 89.
    Lu H et al (2017) Chemotherapy-induced Ca(2+) release stimulates breast Cancer stem cell enrichment. Cell Rep 18:1946–1957. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Radiation OncologyStanford University School of MedicineStanfordUSA
  2. 2.Department of Obstetrics & Gynecologic OncologyStanford University School of MedicineStanfordUSA

Personalised recommendations