Cancer and Metastasis Reviews

, Volume 26, Issue 2, pp 319–331

Hypoxia-driven selection of the metastatic phenotype

Article

Abstract

Intratumoral hypoxia is an independent indicator of poor patient outcome and increasing evidence supports a role for hypoxia in the development of metastatic disease. Studies suggest that the acquisition of the metastatic phenotype is not simply the result of dysregulated signal transduction pathways, but instead is achieved through a stepwise selection process driven by hypoxia. Hypoxia facilitates disruption of tissue integrity through repression of E-cadherin expression, with concomitant gain of N-cadherin expression which allows cells to escape anoikis. Through upregulation of urokinase-type plasminogen activator receptor (uPAR) expression, hypoxia enhances proteolytic activity at the invasive front and alters the interactions between integrins and components of the extracellular matrix, thereby enabling cellular invasion through the basement membrane and the underlying stroma. Cell motility is increased through hypoxia-induced hepatocyte growth factor (HGF)-MET receptor signaling, resulting in cell migration towards the blood or lymphatic microcirculation. Hypoxia-induced vascular endothelial growth factor (VEGF) activity also plays a critical role in the dynamic tumor–stromal interactions required for the subsequent stages of metastasis. VEGF promotes angiogenesis and lymphangiogenesis in the primary tumor, providing the necessary routes for dissemination. VEGF-induced changes in vascular integrity and permeability promote both intravasation and extravasation, while VEGF-induced angiogenesis in the secondary tissue is essential for cell proliferation and establishment of metastatic lesions. Through regulation of these critical molecular targets, hypoxia promotes each step of the metastatic cascade and selects tumor cell populations that are able to escape the unfavorable microenvironment of the primary tumor.

Keywords

Hypoxia Metastasis Invasion Selection HIF 

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References

  1. 1.
    Thomlinson, R. H., & Gray, L. H. (1955). The histological structure of some human lung cancers and the possible implications for radiotherapy. British Journal of Cancer, 9, 539–549.PubMedGoogle Scholar
  2. 2.
    Brown, J. M., & Wilson, W. R. (2004). Exploiting tumour hypoxia in cancer treatment. Nature Reviews. Cancer, 4, 437–447.PubMedGoogle Scholar
  3. 3.
    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
  4. 4.
    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
  5. 5.
    Brizel, D. M., Sibley, G. S., Prosnitz, L. R., Scher, R. L., & Dewhirst, M. W. (1997). Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. International Journal of Radiation Oncology, Biology, Physics, 38, 285–289.PubMedGoogle Scholar
  6. 6.
    Lartigau, E., Randrianarivelo, H., Avril, M. F., Margulis, A., Spatz, A., Eschwege, F., et al. (1997). Intratumoral oxygen tension in metastatic melanoma. Melanoma Research, 7, 400–406.PubMedGoogle Scholar
  7. 7.
    Movsas, B., Chapman, J. D., Greenberg, R. E., Hanlon, A. L., Horwitz, E. M., Pinover, W. H., et al. (2000). Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age: An Eppendorf pO(2) study. Cancer, 89, 2018–2024.PubMedGoogle Scholar
  8. 8.
    Movsas, B., Chapman, J. D., Horwitz, E. M., Pinover, W. H., Greenberg, R. E., Hanlon, A. L., et al. (1999). Hypoxic regions exist in human prostate carcinoma. Urology, 53, 11–18.PubMedGoogle Scholar
  9. 9.
    Hill, R. P. (1990). Tumor progression: Potential role of unstable genomic changes. Cancer Metastasis Reviews, 9, 137–147.PubMedGoogle Scholar
  10. 10.
    Weidner, N., Semple, J. P., Welch, W. R., & Folkman, J. (1991). Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. New England Journal of Medicine, 324, 1–8.PubMedGoogle Scholar
  11. 11.
    Weidner, N. (1993). Tumor angiogenesis: Review of current applications in tumor prognostication. Seminars in Diagnostic Pathology, 10, 302–313.PubMedGoogle Scholar
  12. 12.
    Hockel, M., Schlenger, K., Hockel, S., & Vaupel, P. (1999). Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Research, 59, 4525–4528.PubMedGoogle Scholar
  13. 13.
    Sundfor, K., Lyng, H., & Rofstad, E. K. (1998). Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. British Journal of Cancer, 78, 822–827.PubMedGoogle Scholar
  14. 14.
    Young, S. D., Marshall, R. S., & Hill, R. P. (1988). Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proceedings of the National Academy of Sciences of the United States of America, 85, 9533–9537.PubMedGoogle Scholar
  15. 15.
    Young, S. D., & Hill, R. P. (1990). Effects of reoxygenation on cells from hypoxic regions of solid tumors: Anticancer drug sensitivity and metastatic potential. Journal of the National Cancer Institute, 82, 371–380.PubMedGoogle Scholar
  16. 16.
    Cairns, R. A., Kalliomaki, T., & Hill, R. P. (2001). Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Research, 61, 8903–8908.PubMedGoogle Scholar
  17. 17.
    Postovit, L. M., Adams, M. A., Lash, G. E., Heaton, J. P., & Graham, C. H. (2002). Oxygen-mediated regulation of tumor cell invasiveness. Involvement of a nitric oxide signaling pathway. Journal of Biological Chemistry, 277, 35730–35737.PubMedGoogle Scholar
  18. 18.
    Rofstad, E. K., Rasmussen, H., Galappathi, K., Mathiesen, B., Nilsen, K., & Graff, B. A. (2002). Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor. Cancer Research, 62, 1847–1853.PubMedGoogle Scholar
  19. 19.
    Gatenby, R. A., & Gillies, R. J. (2004). Why do cancers have high aerobic glycolysis? Nature Reviews. Cancer, 4, 891–899.PubMedGoogle Scholar
  20. 20.
    Jiang, B. H., Agani, F., Passaniti, A., & Semenza, G. L. (1997). V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: Involvement of HIF-1 in tumor progression. Cancer Research, 57, 5328–5335.PubMedGoogle Scholar
  21. 21.
    Maxwell, P. H., Dachs, G. U., Gleadle, J. M., Nicholls, L. G., Harris, A. L., Stratford, I. J., et al. (1997). Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 94, 8104–8109.PubMedGoogle Scholar
  22. 22.
    Semenza, G. L. (2003). Targeting HIF-1 for cancer therapy. Nature Reviews. Cancer, 3, 721–732.PubMedGoogle Scholar
  23. 23.
    Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America, 92, 5510–5514.PubMedGoogle Scholar
  24. 24.
    Cockman, M. E., Masson, N., Mole, D. R., Jaakkola, P., Chang, G. W., Clifford, S. C., et al. (2000). Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel–Lindau tumor suppressor protein. Journal of Biological Chemistry, 275, 25733–25741.PubMedGoogle Scholar
  25. 25.
    Maxwell, P. H., Wiesener, M. S., Chang, G. W., Clifford, S. C., Vaux, E. C., Cockman, M. E., et al. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399, 271–275.PubMedGoogle Scholar
  26. 26.
    Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002). Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science, 295, 858–861.PubMedGoogle Scholar
  27. 27.
    Hirota, K., & Semenza, G. L. (2005). Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases. Biochemical and Biophysical Research Communications, 338, 610–616.PubMedGoogle Scholar
  28. 28.
    Harris, A. L. (2002). Hypoxia—A key regulatory factor in tumour growth. Nature Reviews. Cancer, 2, 38–47.PubMedGoogle Scholar
  29. 29.
    Royds, J. A., Dower, S. K., Qwarnstrom, E. E., & Lewis, C. E. (1998). Response of tumour cells to hypoxia: Role of p53 and NFkB. Molecular Pathology, 51, 55–61.PubMedGoogle Scholar
  30. 30.
    Damert, A., Ikeda, E., & Risau, W. (1997). Activator-protein-1 binding potentiates the hypoxia-induciblefactor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells. Biochemical Journal, 327(Pt 2), 419–423.PubMedGoogle Scholar
  31. 31.
    Yamashita, K., Discher, D. J., Hu, J., Bishopric, N. H., & Webster, K. A. (2001). Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. Journal of Biological Chemistry, 276, 12645–12653.PubMedGoogle Scholar
  32. 32.
    Kimura, H., Weisz, A., Kurashima, Y., Hashimoto, K., Ogura, T., D’Acquisto, F., et al. (2000). Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: Control of hypoxia-inducible factor-1 activity by nitric oxide. Blood, 95, 189–197.PubMedGoogle Scholar
  33. 33.
    Norris, M. L., & Millhorn, D. E. (1995). Hypoxia-induced protein binding to O2-responsive sequences on the tyrosine hydroxylase gene. Journal of Biological Chemistry, 270, 23774–23779.PubMedGoogle Scholar
  34. 34.
    Michiels, C., Minet, E., Michel, G., Mottet, D., Piret, J. P., & Raes, M. (2001). HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: Role of MAP kinases. IUBMB Life, 52, 49–53.PubMedGoogle Scholar
  35. 35.
    Seta, K. A., Spicer, Z., Yuan, Y., Lu, G., & Millhorn, D. E. (2002). Responding to hypoxia: Lessons from a model cell line. Science’s Signal Transduction Knowledge Environment, 2002, RE11.Google Scholar
  36. 36.
    Richard, D. E., Berra, E., Gothie, E., Roux, D., & Pouyssegur, J. (1999). p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. Journal of Biological Chemistry, 274, 32631–32637.PubMedGoogle Scholar
  37. 37.
    Brader, S., & Eccles, S. A. (2004). Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori, 90, 2–8.PubMedGoogle Scholar
  38. 38.
    Simon, M. C. (2006). Mitochondrial reactive oxygen species are required for hypoxic HIF alpha stabilization. Advances in Experimental Medicine and Biology, 588, 165–170.PubMedGoogle Scholar
  39. 39.
    Guzy, R. D., & Schumacker, P. T. (2006). Oxygen sensing by mitochondria at complex III: The paradox of increased reactive oxygen species during hypoxia. Experimental Physiology, 91, 807–819.PubMedGoogle Scholar
  40. 40.
    Liu, Y., Christou, H., Morita, T., Laughner, E., Semenza, G. L., & Kourembanas, S. (1998). Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothelial growth factor gene via the 5′ enhancer. Journal of Biological Chemistry, 273, 15257–15262.PubMedGoogle Scholar
  41. 41.
    Huang, L. E., Willmore, W. G., Gu, J., Goldberg, M. A., & Bunn, H. F. (1999). Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling. Journal of Biological Chemistry, 274, 9038–9044.PubMedGoogle Scholar
  42. 42.
    Postovit, L. M., Sullivan, R., Adams, M. A., & Graham, C. H. (2005). Nitric oxide signalling and cellular adaptations to changes in oxygenation. Toxicology, 208, 235–248.PubMedGoogle Scholar
  43. 43.
    Bienz, M. (2005). Beta-catenin: A pivot between cell adhesion and Wnt signalling. Current Biology, 15, R64–R67.PubMedGoogle Scholar
  44. 44.
    Graff, J. R., Gabrielson, E., Fujii, H., Baylin, S. B., & Herman, J. G. (2000). Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. Journal of Biological Chemistry, 275, 2727–2732.PubMedGoogle 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.PubMedGoogle Scholar
  46. 46.
    Imai, T., Horiuchi, A., Wang, C., Oka, K., Ohira, S., Nikaido, T., et al. (2003). Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. American Journal of Pathology, 163, 1437–1447.PubMedGoogle Scholar
  47. 47.
    Bates, R. C., & Mercurio, A. M. (2005). The epithelial–mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biotherapy, 4, 365–370.Google Scholar
  48. 48.
    Kurrey, N. K. K. A., & Bapat, S. A. (2005). Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecologic Oncology, 97, 155–165.PubMedGoogle Scholar
  49. 49.
    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.PubMedGoogle Scholar
  50. 50.
    Luo, Y., He, D. L., Ning, L., Shen, S. L., Li, L., & Li, X. (2006). Hypoxia-inducible factor-1alpha induces the epithelial–mesenchymal transition of human prostatecancer cells. Chinese Medical Journal (English), 119, 713–718.Google Scholar
  51. 51.
    Cano, A., Perez-Moreno, M. A., Rodrigo, I., Locascio, A., Blanco, M. J., del Barrio, M. G., et al. (2000). The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biology, 2, 76–83.PubMedGoogle Scholar
  52. 52.
    Tsutsumi, S., Yanagawa, T., Shimura, T., Kuwano, H., & Raz, A. (2004). Autocrine motility factor signaling enhances pancreatic cancer metastasis. Clinical Cancer Research, 10, 7775–7784.PubMedGoogle Scholar
  53. 53.
    Barrallo-Gimeno, A., & Nieto, M. A. (2005). The Snail genes as inducers of cell movement and survival: Implications in development and cancer. Development, 132, 3151–3161.PubMedGoogle Scholar
  54. 54.
    Li, G., Satyamoorthy, K., & Herlyn, M. (2001). N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Research, 61, 3819–3825.PubMedGoogle Scholar
  55. 55.
    Kuphal, S., & Bosserhoff, A. K. (2006). Influence of the cytoplasmic domain of E-cadherin on endogenous N-cadherin expression in malignant melanoma. Oncogene, 25, 248–259.PubMedGoogle Scholar
  56. 56.
    Kuphal, S., Poser, I., Jobin, C., Hellerbrand, C., & Bosserhoff, A. K. (2004). Loss of E-cadherin leads to upregulation of NF-kappaB activity in malignant melanoma. Oncogene, 23, 8509–8519.PubMedGoogle Scholar
  57. 57.
    Huber, M. A., Beug, H., & Wirth, T. (2004). Epithelial–mesenchymal transition: NF-kappaB takes center stage. Cell Cycle, 3, 1477–1480.PubMedGoogle Scholar
  58. 58.
    Huber, M. A., Azoitei, N., Baumann, B., Grunert, S., Sommer, A., Pehamberger, H., et al. (2004). NF-kappaB is essential for epithelial–mesenchymal transition and metastasis in a model of breast cancer progression. Journal of Clinical Investigation, 114, 569–581.PubMedGoogle Scholar
  59. 59.
    Yebra, M., Parry, G. C., Stromblad, S., Mackman, N., Rosenberg, S., Mueller, B. M., et al. (1996). Requirement of receptor-bound urokinase-type plasminogen activator for integrin alphavbeta5-directed cell migration. Journal of Biological Chemistry, 271, 29393–29399.PubMedGoogle Scholar
  60. 60.
    Waltz, D. A., & Chapman, H. A. (1994). Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. Journal of Biological Chemistry, 269, 14746–14750.PubMedGoogle Scholar
  61. 61.
    Wei, Y., Lukashev, M., Simon, D. I., Bodary, S. C., Rosenberg, S., Doyle, M. V., et al. (1996). Regulation of integrin function by the urokinase receptor. Science, 273, 1551–1555.PubMedGoogle Scholar
  62. 62.
    Pyke, C., Kristensen, P., Ralfkiaer, E., Grondahl-Hansen, J., Eriksen, J., Blasi, F., et al. (1991). Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. American Journal of Pathology, 138, 1059–1067.PubMedGoogle Scholar
  63. 63.
    Duffy, M. J., Maguire, T. M., McDermott, E. W., & O’Higgins, N. (1999). Urokinase plasminogen activator: A prognostic marker in multiple types of cancer. Journal of Surgical Oncology, 71, 130–135.PubMedGoogle Scholar
  64. 64.
    Schmitt, M., Harbeck, N., Thomssen, C., Wilhelm, O., Magdolen, V., Reuning, U., et al. (1997). Clinical impact of the plasminogen activation system in tumor invasion and metastasis: Prognostic relevance and target for therapy. Thrombosis and Haemostasis, 78, 285–296.PubMedGoogle Scholar
  65. 65.
    Kobayashi, H., Fujishiro, S., & Terao, T. (1994). Impact of urokinase-type plasminogen activator and its inhibitor type 1 on prognosis in cervical cancer of the uterus. Cancer Research, 54, 6539–6548.PubMedGoogle Scholar
  66. 66.
    Riethdorf, L., Riethdorf, S., Petersen, S., Bauer, M., Herbst, H., Janicke, F., et al. (1999). Urokinase gene expression indicates early invasive growth in squamous cell lesions of the uterine cervix. Journal of Pathology, 189, 245–250.PubMedGoogle Scholar
  67. 67.
    Yang, J. L., Seetoo, D., Wang, Y., Ranson, M., Berney, C. R., Ham, J. M., et al. (2000). Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets. International Journal of Cancer, 89, 431–439.Google Scholar
  68. 68.
    Graham, C. H., Forsdike, J., Fitzgerald, C. J., & Macdonald-Goodfellow, S. (1999). Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression. International Journal of Cancer, 80, 617–623.Google Scholar
  69. 69.
    Krishnamachary, B., Berg-Dixon, S., Kelly, B., Agani, F., Feldser, D., Ferreira, G., et al. (2003). Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Research, 63, 1138–1143.PubMedGoogle Scholar
  70. 70.
    Rofstad, E. K., Mathiesen, B., Henriksen, K., Kindem, K., & Galappathi, K. (2005). The tumor bed effect: Increased metastatic dissemination from hypoxia-induced up-regulation of metastasis-promoting gene products. Cancer Research, 65, 2387–2396.PubMedGoogle Scholar
  71. 71.
    Graham, C. H., Fitzpatrick, T. E., & McCrae, K. R. (1998). Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway. Blood, 91, 3300–3307.PubMedGoogle Scholar
  72. 72.
    Maity, A., & Solomon, D. (2000). Both increased stability and transcription contribute to the induction of the urokinase plasminogen activator receptor (uPAR) message by hypoxia. Experimental Cell Research, 255, 250–257.PubMedGoogle Scholar
  73. 73.
    Yoon, S. Y., Lee, Y. J., Seo, J. H., Sung, H. J., Park, K. H., Choi, I. K., et al. (2006). uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line. Cell Research, 16, 75–81.PubMedGoogle Scholar
  74. 74.
    Lee, K. H., Choi, E. Y., Hyun, M. S., & Kim, J. R. (2004). Involvement of MAPK pathway in hypoxia-induced up-regulation of urokinase plasminogen activator receptor in a human prostatic cancer cell line, PC3MLN4. Experimental and Molecular Medicine, 36, 57–64.PubMedGoogle Scholar
  75. 75.
    Zagzag, D., Zhong, H., Scalzitti, J. M., Laughner, E., Simons, J. W., & Semenza, G. L. (2000). Expression of hypoxia-inducible factor 1alpha in brain tumors: Association with angiogenesis, invasion, and progression. Cancer, 88, 2606–2618.PubMedGoogle Scholar
  76. 76.
    Zhong, H., De Marzo, A. M., Laughner, E., Lim, M., Hilton, D. A., Zagzag, D., et al. (1999). Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Research, 59, 5830–5835.PubMedGoogle Scholar
  77. 77.
    Trusolino, L., & Comoglio, P. M. (2002). Scatter-factor and semaphorin receptors: Cell signalling for invasive growth. Nature Reviews. Cancer, 2, 289–300.PubMedGoogle Scholar
  78. 78.
    Longati, P., Albero, D., & Comoglio, P. M. (1996). Hepatocyte growth factor is a pleiotropic factor protecting epithelial cells from apoptosis. Cell Death and Differentiation, 3, 23–28.PubMedGoogle Scholar
  79. 79.
    Amicone, L., Spagnoli, F. M., Spath, G., Giordano, S., Tommasini, C., Bernardini, S., et al. (1997). Transgenic expression in the liver of truncated Met blocks apoptosis and permits immortalization of hepatocytes. EMBO Journal, 16, 495–503.PubMedGoogle Scholar
  80. 80.
    Grotegut, S., von Schweinitz, D., Christofori, G., & Lehembre, F. (2006). Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO Journal, 25, 3534–3545.PubMedGoogle Scholar
  81. 81.
    Trusolino, L., Cavassa, S., Angelini, P., Ando, M., Bertotti, A., Comoglio, P. M., et al. (2000). HGF/scatter factor selectively promotes cell invasion by increasing integrin avidity. FASEB Journal, 14, 1629–1640.PubMedGoogle Scholar
  82. 82.
    Ghoussoub, R. A., Dillon, D. A., D’Aquila, T., Rimm, E. B., Fearon, E. R., & Rimm, D. L. (1998). Expression of c-met is a strong independent prognostic factor in breast carcinoma. Cancer, 82, 1513–1520.PubMedGoogle Scholar
  83. 83.
    Camp, R. L., Rimm, E. B., & Rimm, D. L. (1999). Met expression is associated with poor outcome in patients with axillary lymph node negative breast carcinoma. Cancer, 86, 2259–2265.PubMedGoogle Scholar
  84. 84.
    Di Renzo, M. F., Olivero, M., Ferro, S., Prat, M., Bongarzone, I., Pilotti, S., et al. (1992). Overexpression of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene, 7, 2549–2553.PubMedGoogle Scholar
  85. 85.
    Liu, C., Park, M., & Tsao, M. S. (1992). Overexpression of c-met proto-oncogene but not epidermal growth factor receptor or c-erbB-2 in primary human colorectal carcinomas. Oncogene, 7, 181–185.PubMedGoogle Scholar
  86. 86.
    Di Renzo, M. F., Olivero, M., Giacomini, A., Porte, H., Chastre, E., Mirossay, L., et al. (1995). Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clinical Cancer Research, 1, 147–154.PubMedGoogle Scholar
  87. 87.
    Martinez-Rumayor, A., Arrieta, O., Guevara, P., Escobar, E., Rembao, D., Salina, C., et al. (2004). Coexpression of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor cMET predict recurrence of meningiomas. Cancer Letter, 213, 117–124.Google Scholar
  88. 88.
    Kawano, R., Ohshima, K., Karube, K., Yamaguchi, T., Kohno, S., Suzumiya, J., et al. (2004). Prognostic significance of hepatocyte growth factor and c-MET expression in patients with diffuse large B-cell lymphoma. British Journal of Haematology, 127, 305–307.PubMedGoogle Scholar
  89. 89.
    Tsukinoki, K., Yasuda, M., Mori, Y., Asano, S., Naito, H., Ota, Y., et al. (2004). Hepatocyte growth factor and c-Met immunoreactivity are associated with metastasis in high grade salivary gland carcinoma. Oncology Reports, 12, 1017–1021.PubMedGoogle Scholar
  90. 90.
    Rong, S., Segal, S., Anver, M., Resau, J. H., & Vande Woude, G. F. (1994). Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proceedings of the National Academy of Sciences of the United States of America, 91, 4731–4735.PubMedGoogle Scholar
  91. 91.
    Meiners, S., Brinkmann, V., Naundorf, H., & Birchmeier, W. (1998). Role of morphogenetic factors in metastasis of mammary carcinoma cells. Oncogene, 16, 9–20.PubMedGoogle Scholar
  92. 92.
    Jeffers, M., Fiscella, M., Webb, C. P., Anver, M., Koochekpour, S., Vande Woude, G. F. (1998). The mutationally activated Met receptor mediates motility and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 95, 14417–14422.PubMedGoogle Scholar
  93. 93.
    Oh, R. R., Park, J. Y., Lee, J. H., Shin, M. S., Kim, H. S., Lee, S. K., et al. (2002). Expression of HGF/SF and Met protein is associated with genetic alterations of VHL gene in primary renal cell carcinomas. APMIS, 110, 229–238.PubMedGoogle Scholar
  94. 94.
    Koochekpour, S., Jeffers, M., Wang, P. H., Gong, C., Taylor, G. A., Roessler, L. M., et al. (1999). The von Hippel–Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Molecular and Cellular Biology, 19, 5902–5912.PubMedGoogle Scholar
  95. 95.
    Maranchie, J. K., Vasselli, J. R., Riss, J., Bonifacino, J. S., Linehan, W. M., & Klausner, R. D. (2002). The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cells, 1, 247–255.Google Scholar
  96. 96.
    Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., & Comoglio, P. M. (2003). Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cells, 3, 347–361.Google Scholar
  97. 97.
    Chen, H. H., Su, W. C., Lin, P. W., Guo, H. R., & Lee, W. Y. (2006). Hypoxia-inducible factor-1alpha correlates with MET and metastasis in node-negative breast cancer. Breast Cancer Research and Treatment.Google Scholar
  98. 98.
    Scarpino, S., Cancellario, dF., Di Napoli, A., Pasquini, A., Marzullo, A., & Ruco, L. P. (2004). Increased expression of Met protein is associated with up-regulation of hypoxia inducible factor-1 (HIF-1) in tumour cells in papillary carcinoma of the thyroid. Journal of Pathology, 202, 352–358.PubMedGoogle Scholar
  99. 99.
    Ide, T., Kitajima, Y., Miyoshi, A., Ohtsuka, T., Mitsuno, M., Ohtaka, K., et al. (2006). Tumor–stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway. International Journal of Cancer, 119, 2750–2759.Google Scholar
  100. 100.
    Hara, S., Nakashiro, K., Klosek, S. K., Ishikawa, T., Shintani, S., & Hamakawa, H. (2006). Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells. Oral Oncology, 42, 593–598.PubMedGoogle Scholar
  101. 101.
    Boccaccio, C., Gaudino, G., Gambarotta, G., Galimi, F., & Comoglio, P. M. (1994). Hepatocyte growth factor (HGF) receptor expression is inducible and is part of the delayed–early response to HGF. Journal of Biological Chemistry, 269, 12846–12851.PubMedGoogle Scholar
  102. 102.
    Tacchini, L., Dansi, P., Matteucci, E., & Desiderio, M. A. (2001). Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis, 22, 1363–1371.PubMedGoogle Scholar
  103. 103.
    Tacchini, L., Matteucci, E., De Ponti, C., & Desiderio, M. A. (2003). Hepatocyte growth factor signaling regulates transactivation of genes belonging to the plasminogen activation system via hypoxia inducible factor-1. Experimental Cell Research, 290, 391–401.PubMedGoogle Scholar
  104. 104.
    Senger, D. R., Galli, S. J., Dvorak, A. M., Perruzzi, C. A., Harvey, V. S., & Dvorak, H. F. (1983). Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science, 219, 983–985.PubMedGoogle Scholar
  105. 105.
    Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V., & Ferrara, N. (1989). Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 246, 1306–1309.PubMedGoogle Scholar
  106. 106.
    Toi, M., Kondo, S., Suzuki, H., Yamamoto, Y., Inada, K., Imazawa, T., et al. (1996). Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer, 77, 1101–1106.PubMedGoogle Scholar
  107. 107.
    Wong, M. P., Cheung, N., Yuen, S. T., Leung, S. Y., & Chung, L. P. (1999). Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumour progression. International Journal of Cancer, 81, 845–850.Google Scholar
  108. 108.
    Takahashi, Y., Kitadai, Y., Bucana, C. D., Cleary, K. R., & Ellis, L. M. (1995). Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Research, 55, 3964–3968.PubMedGoogle Scholar
  109. 109.
    Toi, M., Hoshina, S., Takayanagi, T., & Tominaga, T. (1994). Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Japanese Journal of Cancer Research, 85, 1045–1049.PubMedGoogle Scholar
  110. 110.
    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.PubMedGoogle Scholar
  111. 111.
    Minchenko, A., Salceda, S., Bauer, T., & Caro, J. (1994). Hypoxia regulatory elements of the human vascular endothelial growth factor gene. Cellular & Molecular Biology Research, 40, 35–39.Google Scholar
  112. 112.
    Forsythe, J. A., Jiang, B. H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., et al. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Molecular and Cellular Biology, 16, 4604–4613.PubMedGoogle Scholar
  113. 113.
    Levy, A. P., Levy, N. S., & Goldberg, M. A. (1996). Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. Journal of Biological Chemistry, 271, 2746–2753.PubMedGoogle Scholar
  114. 114.
    Mizukami, Y., Li, J., Zhang, X., Zimmer, M. A., Iliopoulos, O., & Chung, D. C. (2004). Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Research, 64, 1765–1772.PubMedGoogle Scholar
  115. 115.
    Shinojima, T., Oya, M., Takayanagi, A., Mizuno, R., Shimizu, N., & Murai, M. (2007). Renal cancer cells lacking hypoxia inducible factor (HIF)-1{alpha} expression maintain vascular endothelial growth factor expression through HIF-2{alpha}. Carcinogenesis, 28(3), 529–536.PubMedGoogle Scholar
  116. 116.
    Carmeliet, P., Dor, Y., Herbert, J. M., Fukumura, D., Brusselmans, K., Dewerchin, M., et al. (1998). Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature, 394, 485–490.PubMedGoogle Scholar
  117. 117.
    Ryan, H. E., Lo, J., & Johnson, R. S. (1998). HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO Journal, 17, 3005–3015.PubMedGoogle Scholar
  118. 118.
    Dvorak, H. F., Nagy, J. A., Feng, D., Brown, L. F., & Dvorak, A. M. (1999). Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Current Topics in Microbiology and Immunology, 237, 97–132.PubMedGoogle Scholar
  119. 119.
    Rofstad, E. K., Tunheim, S. H., Mathiesen, B., Graff, B. A., Halsor, E. F., Nilsen, K., et al. (2002). Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts. Cancer Research, 62, 661–664.PubMedGoogle Scholar
  120. 120.
    Jain, R. K. (1998). The next frontier of molecular medicine: Delivery of therapeutics. Nature Medicine, 4, 655–657.Google Scholar
  121. 121.
    Leu, A. J., Berk, D. A., Lymboussaki, A., Alitalo, K., & Jain, R. K. (2000). Absence of functional lymphatics within a murine sarcoma: A molecular and functional evaluation. Cancer Research, 60, 4324–4327.PubMedGoogle Scholar
  122. 122.
    Padera, T. P., Kadambi, A., di Tomaso, E., Carreira, C. M., Brown, E. B., Boucher, Y., et al. (2002). Lymphatic metastasis in the absence of functional intratumor lymphatics. Science, 296, 1883–1886.PubMedGoogle Scholar
  123. 123.
    Boucher, Y., Lee, I., & Jain, R. K. (1995). Lack of general correlation between interstitial fluid pressure and oxygen partial pressure in solid tumors. Microvascular Research, 50, 175–182.PubMedGoogle Scholar
  124. 124.
    Dadiani, M., Kalchenko, V., Yosepovich, A., Margalit, R., Hassid, Y., Degani, H., et al. (2006). Real-time imaging of lymphogenic metastasis in orthotopic human breast cancer. Cancer Research, 66, 8037–8041.PubMedGoogle Scholar
  125. 125.
    Dadiani, M., Margalit, R., Sela, N., & Degani, H. (2004). High-resolution magnetic resonance imaging of disparities in the transcapillary transfer rates in orthotopically inoculated invasive breast tumors. Cancer Research, 64, 3155–3161.PubMedGoogle Scholar
  126. 126.
    Nathanson, S. D. (2003). Insights into the mechanisms of lymph node metastasis. Cancer, 98, 413–423.PubMedGoogle Scholar
  127. 127.
    Fyles, A., Milosevic, M., Pintilie, M., Syed, A., Levin, W., Manchul, L., et al. (2006). Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiotherapy and Oncology, 80, 132–137.PubMedGoogle Scholar
  128. 128.
    Claffey, K. P., Brown, L. F., del Aguila, L. F., Tognazzi, K., Yeo, K. T., Manseau, E. J., et al. (1996). Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Research, 56, 172–181.PubMedGoogle Scholar
  129. 129.
    Esser, S., Lampugnani, M. G., Corada, M., Dejana, E., & Risau, W. (1998). Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. Journal of Cell Science, 111(Pt 13), 1853–1865.PubMedGoogle Scholar
  130. 130.
    Lee, T. H., Avraham, H. K., Jiang, S., & Avraham, S. (2003). Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. Journal of Biological Chemistry, 278, 5277–5284.PubMedGoogle Scholar
  131. 131.
    Kevil, C. G., Payne, D. K., Mire, E., & Alexander, J. S. (1998). Vascular permeability factor/vascular endothelial cell growth factor-mediated permeability occurs through disorganization of endothelial junctional proteins. Journal of Biological Chemistry, 273, 15099–15103.PubMedGoogle Scholar
  132. 132.
    Yuan, F., Chen, Y., Dellian, M., Safabakhsh, N., Ferrara, N., & Jain, R. K. (1996). Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proceedings of the National Academy of Sciences of the United States of America, 93, 14765–14770.PubMedGoogle Scholar
  133. 133.
    Tong, R. T., Boucher, Y., Kozin, S. V., Winkler, F., Hicklin, D. J., & Jain, R. K. (2004). Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Research, 64, 3731–3736.PubMedGoogle Scholar
  134. 134.
    Lee, C. G., Heijn, M., di Tomaso, E., Griffon-Etienne, G., Ancukiewicz, M., Koike, C., et al. (2000). Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Research, 60, 5565–5570.PubMedGoogle Scholar
  135. 135.
    Salnikov, A. V., Heldin, N. E., Stuhr, L. B., Wiig, H., Gerber, H., Reed, R. K., et al. (2006). Inhibition of carcinoma cell-derived VEGF reduces inflammatory characteristics in xenograft carcinoma. International Journal of Cancer, 119, 2795–2802.Google Scholar
  136. 136.
    Willett, C. G., Boucher, Y., di Tomaso, E., Duda, D. G., Munn, L. L., Tong, R. T., et al. (2004). Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Medicine, 10, 145–147.Google Scholar
  137. 137.
    Weis, S., Cui, J., Barnes, L., & Cheresh, D. (2004). Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. Journal of Cell Biology, 167, 223–229.PubMedGoogle Scholar
  138. 138.
    Rofstad, E. K., & Danielsen, T. (1999). Hypoxia-induced metastasis of human melanoma cells: Involvement of vascular endothelial growth factor-mediated angiogenesis. British Journal of Cancer, 80, 1697–1707.PubMedGoogle Scholar
  139. 139.
    Melnyk, O., Shuman, M. A., & Kim, K. J. (1996). Vascular endothelial growth factor promotes tumor dissemination by a mechanism distinct from its effect on primary tumor growth. Cancer Research, 56, 921–924.PubMedGoogle Scholar
  140. 140.
    Chambers, A. F., MacDonald, I. C., Schmidt, E. E., Koop, S., Morris, V. L., Khokha, R., et al. (1995). Steps in tumor metastasis: New concepts from intravital videomicroscopy. Cancer Metastasis Reviews, 14, 279–301.PubMedGoogle Scholar
  141. 141.
    Cuvier, C., Jang, A., & Hill, R. P. (1997). Exposure to hypoxia, glucose starvation and acidosis: Effect on invasive capacity of murine tumor cells and correlation with cathepsin (L + B) secretion. Clinical & Experimental Metastasis, 15, 19–25.Google Scholar
  142. 142.
    Postovit, L. M., Adams, M. A., Lash, G. E., Heaton, J. P., & Graham, C. H. (2004). Nitric oxide-mediated regulation of hypoxia-induced B16F10 melanoma metastasis. International Journal of Cancer, 108, 47–53.Google Scholar
  143. 143.
    Liotta, L. A., Kleinerman, J., & Saidel, G. M. (1974). Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Research, 34, 997–1004.PubMedGoogle Scholar
  144. 144.
    Butler, T. P., & Gullino, P. M. (1975). Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Research, 35, 512–516.PubMedGoogle Scholar
  145. 145.
    Morris, V. L., Koop, S., MacDonald, I. C., Schmidt, E. E., Grattan, M., Percy, D., et al. (1994). Mammary carcinoma cell lines of high and low metastatic potential differ not in extravasation but in subsequent migration and growth. Clinical & Experimental Metastasis, 12, 357–367.Google Scholar
  146. 146.
    Koop, S., MacDonald, I. C., Luzzi, K., Schmidt, E. E., Morris, V. L., Grattan, M., et al. (1995). Fate of melanoma cells entering the microcirculation: Over 80% survive and extravasate. Cancer Research, 55, 2520–2523.PubMedGoogle Scholar
  147. 147.
    Koop, S., Khokha, R., Schmidt, E. E., MacDonald, I. C., Morris, V. L., Chambers, A. F., et al. (1994). Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth. Cancer Research, 54, 4791–4797.PubMedGoogle Scholar
  148. 148.
    Chambers, A. F., MacDonald, I. C., Schmidt, E. E., Morris, V. L., & Groom, A. C. (2000). Clinical targets for anti-metastasis therapy. Advances in Cancer Research, 79, 91–121.PubMedGoogle Scholar
  149. 149.
    Muir, C., Chung, L. W., Carson, D. D., & Farach-Carson, M. C. (2006). Hypoxia increases VEGF-A production by prostate cancer and bone marrow stromal cells and initiates paracrine activation of bone marrow endothelial cells. Clinical & Experimental Metastasis, 23, 75–86.Google Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Anatomy and Cell BiologyQueen’s UniversityKingstonCanada

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