Skip to main content
SpringerLink
Log in

Hypoxia-Induced Phenotypes that Mediate Tumor Heterogeneity

  • Chapter
  • First Online:
Hypoxia and Cancer Metastasis

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1136))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14:611–629. https://doi.org/10.1038/nrclinonc.2017.44

    Article  PubMed  PubMed Central  Google Scholar 

  2. Brown JM, Giaccia AJ (1998) The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 58:1408–1416

    CAS  PubMed  Google Scholar 

  3. Oskarsson T, Batlle E, Massague J (2014) Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14:306–321. https://doi.org/10.1016/j.stem.2014.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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:https://doi.org/10.1126/science.1059796 1059796 [pii]

  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.2008.21

    Google Scholar 

  6. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737

    Article  CAS  PubMed  Google Scholar 

  7. Batlle E, Clevers H (2017) Cancer stem cells revisited. Nat Med 23:1124–1134. https://doi.org/10.1038/nm.4409

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2015.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oliveira-Costa JP et al (2011) Differential expression of HIF-1alpha in CD44+CD24−/low breast ductal carcinomas. Diagn Pathol 6:73. https://doi.org/10.1186/1746-1596-6-73

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2011.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li Z et al (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501–513. https://doi.org/10.1016/j.ccr.2009.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1421438111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1186/bcr3087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1158/1078-0432.CCR-16-1678

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1182/blood-2011-10-387381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mallard BW, Tiralongo J (2017) Cancer stem cell marker glycosylation: nature, function and significance. Glycoconj J 34:441–452. https://doi.org/10.1007/s10719-017-9780-9

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2016.11.004

    Article  CAS  PubMed  Google Scholar 

  18. Glumac PM, LeBeau AM (2018) The role of CD133 in cancer: a concise review. Clin Transl Med 7:18. https://doi.org/10.1186/s40169-018-0198-1

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.2353/ajpath.2010.091021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/onc.2009.252

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.3892/ijo.2011.1207

    Article  CAS  PubMed  Google Scholar 

  22. Ohnishi S et al (2013) Hypoxia-inducible factors activate CD133 promoter through ETS family transcription factors. PLoS One 8:e66255. https://doi.org/10.1371/journal.pone.0066255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1113960109

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2011.06.005

    Article  CAS  PubMed  Google Scholar 

  25. Thomas S et al (2012) CD24 is an effector of HIF-1-driven primary tumor growth and metastasis. Cancer Res 72:5600–5612. https://doi.org/10.1158/0008-5472.CAN-11-3666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2014.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.celrep.2017.07.049

    Article  CAS  PubMed  Google Scholar 

  28. Boiani M, Scholer HR (2005) Regulatory networks in embryo-derived pluripotent stem cells. Nat Rev Mol Cell Biol 6:872–884. https://doi.org/10.1038/nrm1744

    Article  CAS  PubMed  Google Scholar 

  29. Boyer LA et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956. https://doi.org/10.1016/j.cell.2005.08.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/ng.127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu T et al (2008) Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res 68:6533–6540. https://doi.org/10.1158/0008-5472.CAN-07-6642

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1084/jem.20100797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1101/gad.1769609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2009.08.018

    Article  CAS  PubMed  Google Scholar 

  35. Jeter CR et al (2009) Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 27:993–1005. https://doi.org/10.1002/stem.29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cowden Dahl KD et al (2005) Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation. Mol Cell Biol 25:10479–10491. https://doi.org/10.1128/MCB.25.23.10479-10491.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1101/gad.1399906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mathieu J et al (2011) HIF induces human embryonic stem cell markers in cancer cells. Cancer Res 71:4640–4652. https://doi.org/10.1158/0008-5472.CAN-10-3320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 6:1078–1088

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kumar SM et al (2012) Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene 31:4898–4911. https://doi.org/10.1038/onc.2011.656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Seo EJ et al (2016) Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer. Oncotarget 7:55624–55638. https://doi.org/10.18632/oncotarget.10954

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1809695115

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1073/pnas.1513433112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1602883113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Meyer KD, Jaffrey SR (2014) The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol 15:313–326. https://doi.org/10.1038/nrm3785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Geula S et al (2015) Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347:1002–1006. https://doi.org/10.1126/science.1261417

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nrclinonc.2015.61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Keith B, Simon MC (2007) Hypoxia-inducible factors, stem cells, and cancer. Cell 129:465–472. https://doi.org/10.1016/j.cell.2007.04.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776

    Article  CAS  PubMed  Google Scholar 

  50. Gustafsson MV et al (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9:617–628. https://doi.org/10.1016/j.devcel.2005.09.010

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/cdd.2011.95

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2017.10.005

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/srep22966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Giambra V et al (2015) Leukemia stem cells in T-ALL require active Hif1alpha and wnt signaling. Blood 125:3917–3927. https://doi.org/10.1182/blood-2014-10-609370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/onc.2017.404

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/s41598-017-09244-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1186/s13058-018-0944-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.2011.02.013

    Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-16-0530

    Article  CAS  PubMed  Google Scholar 

  60. Luo M et al (2018) Targeting breast Cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab 28:69–86 e66. https://doi.org/10.1016/j.cmet.2018.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.cmet.2017.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.celrep.2014.12.032

    Article  CAS  PubMed  Google Scholar 

  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-05-3719

    Google Scholar 

  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/ncb1691

    Google Scholar 

  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)63501-8

    Google Scholar 

  66. Rankin EB, Giaccia AJ (2016) Hypoxic control of metastasis. Science 352:175–180. https://doi.org/10.1126/science.aaf4405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.18632/oncotarget.14484

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1801348115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lupia M, Cavallaro U (2017) Ovarian cancer stem cells: still an elusive entity? Mol Cancer 16:64. https://doi.org/10.1186/s12943-017-0638-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1002/stem.1816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.semcancer.2018.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.4049/jimmunol.1302140

    Article  CAS  PubMed  Google Scholar 

  73. Wei J et al (2011) Hypoxia potentiates glioma-mediated immunosuppression. PLoS One 6:e16195. https://doi.org/10.1371/journal.pone.0016195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.coi.2012.01.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1520032112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1718197115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 8:1831–1837

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s10549-007-9742-1

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/onc.2011.122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nrc1524

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-16-0579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chiou SH et al (2017) BLIMP1 induces transient metastatic heterogeneity in pancreatic Cancer. Cancer Discov 7:1184–1199. https://doi.org/10.1158/2159-8290.CD-17-0250

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/S1470-2045(08)70076-7

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1158/1078-0432.CCR-05-2690

    Article  CAS  PubMed  Google Scholar 

  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 53:1192–1202

    Article  CAS  PubMed  Google Scholar 

  86. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410. https://doi.org/10.1038/nrc3064

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/1078-0432.CCR-12-2986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cao Y et al (2013) Tumor cells upregulate normoxic HIF-1alpha in response to doxorubicin. Cancer Res 73:6230–6242. https://doi.org/10.1158/0008-5472.CAN-12-1345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lu H et al (2017) Chemotherapy-induced Ca(2+) release stimulates breast Cancer stem cell enrichment. Cell Rep 18:1946–1957. https://doi.org/10.1016/j.celrep.2017.02.001

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA

    Jin Qian & Erinn B. Rankin

  2. Department of Obstetrics & Gynecologic Oncology, Stanford University School of Medicine, Stanford, CA, USA

    Erinn B. Rankin

Authors
  1. Jin Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erinn B. Rankin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erinn B. Rankin .

Editor information

Editors and Affiliations

  1. Breast and Ovarian Cancer Program, Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniele M. Gilkes

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Qian, J., Rankin, E.B. (2019). Hypoxia-Induced Phenotypes that Mediate Tumor Heterogeneity. In: Gilkes, D. (eds) Hypoxia and Cancer Metastasis. Advances in Experimental Medicine and Biology, vol 1136. Springer, Cham. https://doi.org/10.1007/978-3-030-12734-3_3

Download citation

Publish with us

Policies and ethics

Search

Navigation