Cancer and Metastasis Reviews

, Volume 26, Issue 2, pp 333–339 | Cite as

Hypoxia, gene expression, and metastasis

  • Denise A. Chan
  • Amato J. GiacciaEmail author


Hypoxia poses many problems to the treatment of cancer. Hypoxic tumors are more resistant to chemotherapy and radiation. In addition, hypoxia induces a number of genes responsible for increased invasion, aggressiveness, and metastasis of tumors. The augmented metastatic potential due to hypoxia-mediated gene expression is discussed in this section. Particular attention is given to recent studies of specific genes involved in the key steps of metastasis, including extracellular matrix interactions, migration, and proliferation.


Hypoxia Hypoxia-inducible factor Metastasis Angiogenesis Radiotherapy Chemotherapy 


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  1. 1.
    Brown, J. M., & Giaccia, A. J. (1998). The unique physiology of solid tumors: Opportunities (and problems) for cancer therapy. Cancer Research, 58, 1408–1416.PubMedGoogle Scholar
  2. 2.
    Hockel, M., Schlenger, K., Knoop, C., & Vaupel, P. (1991). Oxygenation of carcinomas of the uterine cervix: Evaluation by computerized O2 tension measurements. Cancer Research, 51, 6098–6102.PubMedGoogle Scholar
  3. 3.
    Folkman, J. (1992). The role of angiogenesis in tumor growth. Seminars in Cancer Biology, 3, 65–71.PubMedGoogle Scholar
  4. 4.
    Shweiki, D., Itin, A., Soffer, D., & Keshet, E. (1992). Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature, 359, 843–845.PubMedCrossRefGoogle Scholar
  5. 5.
    Grunt, T. W., Lametschwandtner, A., & Staindl, O. (1985). The vascular pattern of basal cell tumors: Light microscopy and scanning electron microscopic study on vascular corrosion casts. Microvascular Research, 29, 371–386.PubMedCrossRefGoogle Scholar
  6. 6.
    Dewhirst, M. W., Tso, C. Y., Oliver, R., Gustafson, C. S., Secomb, T. W., & Gross, J. F. (1989). Morphologic and hemodynamic comparison of tumor and healing normal tissue microvasculature. International Journal of Radiation Oncology, Biology, Physics, 17, 91–99.PubMedGoogle Scholar
  7. 7.
    Shah-Yukich, A. A., & Nelson, A. C. (1988). Characterization of solid tumor microvasculature: A three-dimensional analysis using the polymer casting technique. Laboratory Investigation, 58, 236–244.PubMedGoogle Scholar
  8. 8.
    Endrich, B., Reinhold, H. S., Gross, J. F., & Intaglietta, M. (1979). Tissue perfusion inhomogeneity during early tumor growth in rats. Journal of the National Cancer Institute, 62, 387–395.PubMedGoogle Scholar
  9. 9.
    Tannock, I. F. (1968). The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. British Journal of Cancer, 22, 258–273.PubMedGoogle Scholar
  10. 10.
    Kallman, R. F., & Dorie, M. J. (1986). Tumor oxygenation and reoxygenation during radiation therapy: Their importance in predicting tumor response. International Journal of Radiation Oncology, Biology, Physics, 12, 681–685.PubMedGoogle Scholar
  11. 11.
    Hall, E. J. (1994). Molecular biology in radiation therapy: The potential impact of recombinant technology on clinical practice. International Journal of Radiation Oncology, Biology, Physics, 30, 1019–1028.PubMedGoogle Scholar
  12. 12.
    Comerford, K. M., Wallace, T. J., Karhausen, J., Louis, N. A., Montalto, M. C., & Colgan, S. P. (2002). Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Research, 62, 3387–3394.PubMedGoogle Scholar
  13. 13.
    Wartenberg, M., Ling, F. C., Muschen, M., Klein, F., Acker, H., Gassmann, M., et al. (2003). Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. FASEB Journal, 17, 503–505.PubMedGoogle Scholar
  14. 14.
    Graeber, T. G., Osmanian, C., Jacks, T., Housman, D. E., Koch, C. J., Lowe, S. W., et al. (1996). Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature, 379, 88–91.PubMedCrossRefGoogle Scholar
  15. 15.
    Soengas, M. S., Alarcon, R. M., Yoshida, H., Giaccia, A. J., Hakem, R., Mak, T. W., et al. (1999). Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science, 284, 156–159.PubMedCrossRefGoogle Scholar
  16. 16.
    Lowe, S. W., Bodis, S., McClatchey, A., Remington, L., Ruley, H. E., Fisher, D. E., et al. (1994). p53 status and the efficacy of cancer therapy in vivo. Science, 266, 807–810.PubMedCrossRefGoogle Scholar
  17. 17.
    Bindra, R. S., & Glazer, P. M. (2005). Genetic instability and the tumor microenvironment: Towards the concept of microenvironment-induced mutagenesis. Mutation Research, 569, 75–85.PubMedGoogle Scholar
  18. 18.
    Bindra, R. S., & Glazer, P. M. (2007). Co-repression of mismatch repair gene expression by hypoxia in cancer cells: Role of the Myc/Max network. Cancer Letter (in press).Google Scholar
  19. 19.
    Huang, L. E., Bindra, R. S., Glazer, P. M., & Harris, A. L. (2007). Hypoxia-induced genetic instability-a calculated mechanism underlying tumor progression. Journal of Molecular Medicine, 85, 139–148.PubMedCrossRefGoogle Scholar
  20. 20.
    Koshiji, M., To, K. K., Hammer, S., Kumamoto, K., Harris, A. L., Modrich, P., et al. (2005). HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Molecular Cell, 17, 793–803.PubMedCrossRefGoogle Scholar
  21. 21.
    Hockel, M., Knoop, C., Schlenger, K., Vorndran, B., Baussmann, E., Mitze, M., et al. (1993). Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiotherapy and Oncology, 26, 45–50.PubMedCrossRefGoogle Scholar
  22. 22.
    Brizel, D. M., Scully, S. P., Harrelson, J. M., Layfield, L. J., Bean, J. M., Prosnitz, L. R., et al. (1996). Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Research, 56, 941–943.PubMedGoogle Scholar
  23. 23.
    Hockel, M., Schlenger, K., Aral, B., Mitze, M., Schaffer, U., & Vaupel, P. (1996). Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Research, 56, 4509–4515.PubMedGoogle Scholar
  24. 24.
    Fyles, A. W., Milosevic, M., Wong, R., Kavanagh, M. C., Pintilie, M., Sun, A., et al. (1998). Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiotherapy and Oncology, 48, 149–156.PubMedCrossRefGoogle Scholar
  25. 25.
    Nordsmark, M., Hoyer, M., Keller, J., Nielsen, O. S., Jensen, O. M., & Overgaard, J. (1996). The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas. International Journal of Radiation Oncology, Biology, Physics, 35, 701–708.PubMedCrossRefGoogle Scholar
  26. 26.
    Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., et al. (2001). HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science, 292, 464–468.PubMedGoogle Scholar
  27. 27.
    Jaakkola, P., Mole, D. R., Tian, Y. M., Wilson, M. I., Gielbert, J., Gaskell, S. J., et al. (2001). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292, 468–472.PubMedGoogle Scholar
  28. 28.
    Yu, F., White, S. B., Zhao, Q., & Lee, F. S. (2001). HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proceedings of the National Academy of Sciences of the USA, 98, 9630–9635.PubMedCrossRefGoogle Scholar
  29. 29.
    Huang, L. E., Gu, J., Schau, M., & Bunn, H. F. (1998). Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proceedings of the National Academy of Sciences of the USA, 95, 7987–7992.PubMedCrossRefGoogle Scholar
  30. 30.
    Masson, N., Willam, C., Maxwell, P. H., Pugh, C. W., & Ratcliffe, P. J. (2001). Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO Journal, 20, 5197–5206.PubMedCrossRefGoogle Scholar
  31. 31.
    Chan, D. A., Sutphin, P. D., Denko, N. C., & Giaccia, A. J. (2002). Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. Journal of Biological Chemistry, 277, 40112–40117.PubMedCrossRefGoogle Scholar
  32. 32.
    Chan, D. A., Sutphin, P. D., Yen, S. E., & Giaccia, A. J. (2005). Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1 alpha. Molecular and Cellular Biology, 25, 6415–6426.PubMedCrossRefGoogle Scholar
  33. 33.
    Epstein, A. C., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O’Rourke, J., Mole, D. R., et al. (2001). C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 107, 43–54.PubMedCrossRefGoogle Scholar
  34. 34.
    Bruick, R. K., & McKnight, S. L. (2001). A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 294, 1337–1340.PubMedCrossRefGoogle Scholar
  35. 35.
    Semenza, G. L. (1999). Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annual Review of Cell and Development Biology, 15, 551–578.CrossRefGoogle Scholar
  36. 36.
    Hickey, M. M., & Simon, M. C. (2006). Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Current Topics in Developmental Biology, 76, 217–257.PubMedGoogle Scholar
  37. 37.
    Brahimi-Horn, M. C., & Pouyssegur, J. (2007). Harnessing the hypoxia-inducible factor in cancer and ischemic disease. Biochemical Pharmacology, 73, 450–457.PubMedCrossRefGoogle Scholar
  38. 38.
    Denko, N. C., Fontana, L. A., Hudson, K. M., Sutphin, P. D., Raychaudhuri, S., Altman, R., et al. (2003). Investigating hypoxic tumor physiology through gene expression patterns. Oncogene, 22, 5907–5914.PubMedCrossRefGoogle Scholar
  39. 39.
    Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q. T., et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440, 1222–1226.PubMedCrossRefGoogle Scholar
  40. 40.
    Erler, J. T., & Giaccia, A. J. (2006). Lysyl oxidase mediates hypoxic control of metastasis. Cancer Research, 66, 10238–10241.PubMedCrossRefGoogle Scholar
  41. 41.
    Higgins, D. F., Biju, M. P., Akai, Y., Wutz, A., Johnson, R. S., & Haase, V. H. (2004). Hypoxic induction of Ctgf is directly mediated by Hif-1. American Journal of Physiology. Renal Physiology, 287, F1223–F1232.PubMedCrossRefGoogle Scholar
  42. 42.
    Wenger, C., Ellenrieder, V., Alber, B., Lacher, U., Menke, A., Hameister, H., et al. (1999). Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells. Oncogene, 18, 1073–1080.PubMedCrossRefGoogle Scholar
  43. 43.
    Dornhofer, N., Spong, S., Bennewith, K., Salim, A., Klaus, S., Kambham, N., et al. (2006). Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Research, 66, 5816–5827.PubMedCrossRefGoogle Scholar
  44. 44.
    Aikawa, T., Gunn, J., Spong, S. M., Klaus, S. J., & Korc, M. (2006). Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer. Molecular Cancer Therapeutic, 5, 1108–1116.CrossRefGoogle Scholar
  45. 45.
    Krishnamachary, B., Zagzag, D., Nagasawa, H., Rainey, K., Okuyama, H., Baek, J. H., 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 Research, 66, 2725–2731.PubMedCrossRefGoogle Scholar
  46. 46.
    Esteban, M. A., Tran, M. G., Harten, S. K., Hill, P., Castellanos, M. C., Chandra, A., et al. (2006). Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Research, 66, 3567–3575.PubMedCrossRefGoogle Scholar
  47. 47.
    Evans, A. J., Russell, R. C., Roche, O., Burry, T. N., Fish, J. E., Chow, V. W., et al. (2007). VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Molecular and Cellular Biology, 27, 157–169.PubMedCrossRefGoogle Scholar
  48. 48.
    Wang, J., Loberg, R., & Taichman, R. S. (2006). The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis. Cancer Metastasis Reviews, 25, 573–587.PubMedGoogle Scholar
  49. 49.
    Pore, N., & Maity, A. (2006). The Chemokine Receptor CXCR4: A Homing Device for Hypoxic Cancer Cells? Cancer Biology and Therapy, 5, 1563–1565.PubMedCrossRefGoogle Scholar
  50. 50.
    Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410, 50–56.PubMedCrossRefGoogle Scholar
  51. 51.
    Staller, P., Sulitkova, J., Lisztwan, J., Moch, H., Oakeley, E. J., & Krek, W. (2003). Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature, 425, 307–311.PubMedCrossRefGoogle Scholar
  52. 52.
    Cooper, C. R., Sikes, R. A., Nicholson, B. E., Sun, Y. X., Pienta, K. J., & Taichman, R. S. (2004). Cancer cells homing to bone: the significance of chemotaxis and cell adhesion. Cancer Treatment and Research, 118, 291–309.PubMedGoogle Scholar
  53. 53.
    Taichman, R. S., Cooper, C., Keller, E. T., Pienta, K. J., Taichman, N. S., & McCauley, L. K. (2002). Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Research, 62, 1832–1837.PubMedGoogle Scholar
  54. 54.
    Robledo, M. M., Bartolome, R. A., Longo, N., Rodriguez-Frade, J. M., Mellado, M., Longo, I., et al. (2001). Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. Journal of Biological Chemistry, 276, 45098–45105.PubMedCrossRefGoogle Scholar
  55. 55.
    Scala, S., Ottaiano, A., Ascierto, P. A., Cavalli, M., Simeone, E., Giuliano, P., et al. (2005). Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma. Clinical Cancer Research, 11, 1835–1841.PubMedCrossRefGoogle Scholar
  56. 56.
    Longo-Imedio, M. I., Longo, N., Trevino, I., Lazaro, P., & Sanchez-Mateos, P. (2005). Clinical significance of CXCR3 and CXCR4 expression in primary melanoma. International Journal of Cancer, 117, 861–865.CrossRefGoogle Scholar
  57. 57.
    Scala, S., Giuliano, P., Ascierto, P. A., Ierano, C., Franco, R., Napolitano, M., et al. (2006). Human melanoma metastases express functional CXCR4. Clinical Cancer Research, 12, 2427–2433.PubMedCrossRefGoogle Scholar
  58. 58.
    Ceradini, D. J., Kulkarni, A. R., Callaghan, M. J., Tepper, O. M., Bastidas, N., Kleinman, M. E., et al. (2004). Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Medicine, 10, 858–864.PubMedCrossRefGoogle Scholar
  59. 59.
    Welford, S. M., Bedogni, B., Gradin, K., Poellinger, L., Broome Powell, M., & Giaccia, A. J. (2006). HIF1alpha delays premature senescence through the activation of MIF. Genes & Development, 20, 3366–3371.CrossRefGoogle Scholar
  60. 60.
    Lal, A., Peters, H., St Croix, B., Haroon, Z. A., Dewhirst, M. W., Strausberg, R. L., et al. (2001). Transcriptional response to hypoxia in human tumors. Journal of the National Cancer Institute, 93, 1337–1343.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Radiation Oncology, Division of Cancer and Radiation BiologyStanford University School of MedicineStanfordUSA

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