Skip to main content
SpringerLink
Log in

Hypoxic gene expression and metastasis

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Solid tumors possess malformed vasculature that results in the exposure of tumor cells to a low oxygen environment. Tumor hypoxia has been demonstrated in human and mouse tumors through the use of oxygen microelectrodes, hypoxic specific biomarkers, specific transcriptional changes induced by hypoxia, and secreted proteins. While many elegant experiments have demonstrated that hypoxia enhances metastatic potential, it is still unknown what mechanisms are involved in this enhancement. In this review, we discuss the clinical and basic science studies that support an important role for hypoxia in increasing the metastatic potential of tumor cells by promoting tissue remodeling, inducing angiogenesis and reducing apoptosis. Particular emphasis is given to recent findings that provide insight to the role of hypoxia in the metastatic process.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    PubMed  Google Scholar 

  2. Thomlinson RH, Gray LH: The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9: 539–549, 1955

    PubMed  Google Scholar 

  3. Kennedy KA, Teicher BA, Rockwell S, Sartorelli AC: The hypoxic tumor cell: A target for selective cancer chemotherapy. Biochem Pharmacol 29: 1–8, 1980

    PubMed  Google Scholar 

  4. Harris AL: Hypoxia-a key regulatory factor in tumor growth. Nat Rev Cancer 2: 38–47, 2002

    PubMed  Google Scholar 

  5. Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, Broder GJ: Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 14: 831–838, 1988

    PubMed  Google Scholar 

  6. Wendling P, Manz R, Thews G, Vaupel P: Heterogeneous oxygenation of rectal carcinomas in humans: A critical parameter for preoperative irradiation? Adv Exp Med Biol 180: 293–300, 1984

    PubMed  Google Scholar 

  7. Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, Vaupel P: Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26: 45–50, 1993

    PubMed  Google Scholar 

  8. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P: Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56: 4509–4515, 1996

    PubMed  Google Scholar 

  9. Fyles A, Milosevic M, Hedley D, Pintilie M, Levin W, Manchul L, Hill RP: Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. J Clin Oncol 20: 680–687, 2002

    PubMed  Google Scholar 

  10. Movsas B, Chapman JD, Hanlon AL, Horwitz EM, Greenberg RE, Stobbe C, Hanks GE, Pollack A: Hypoxic prostate/muscle pO2 ratio predicts for biochemical failure in patients with prostate cancer: Preliminary findings. Urology 60: 634–639, 2002

    PubMed  Google Scholar 

  11. Rofstad EK, Sundfor K, Lyng H, Trope CG: Hypoxiainduced treatment failure in advanced squamous cell carci-noma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxiainduced metastasis. Br J Cancer 83: 354–359, 2000

    PubMed  Google Scholar 

  12. Brizel DM, Scully SP, Harrelson JM: Tumor oxygenation predicts for likelihood of distant metastasis in human soft tissue sarcoma. Cancer Res 56: 941–943, 1996

    PubMed  Google Scholar 

  13. Nordsmark M, Alsner J, Keller J, Nielsen OS, Jensen OM, Horsman MR, Overgaard J: Hypoxia in human soft tissue sarcomas: Adverse impact on survival and no association with p53 mutations. Br J Cancer 84: 1070–1075, 2001

    PubMed  Google Scholar 

  14. Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, Harris AL: Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19: 3660–3668, 2001

    PubMed  Google Scholar 

  15. Swinson DE, Jones JL, Richardson D, Wykoff C, Turley H, Pastorek J, Taub N, Harris AL, O'Byrne KJ: Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol 21: 473–482, 2003

    PubMed  Google Scholar 

  16. Loncaster JA, Harris AL, Davidson SE, Logue JP, Hunter RD, Wycoff CC, Pastorek J, Ratcliffe PJ, Stratford IJ, West CM: Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: Correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 61: 6394–6399, 2001

    PubMed  Google Scholar 

  17. Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, Gatter KC, AL. H: Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumors and survival. Br J Cancer 85: 881–890, 2001

    PubMed  Google Scholar 

  18. Kaelin WG Jr.: How oxygen makes its presence felt. Genes Dev 16: 1441–1445, 2002

    PubMed  Google Scholar 

  19. Giaccia A, Siim BG, Johnson RS: HIF-1 as a target for drug development. Nat Rev Drug Discov 2: 803–811, 2003

    PubMed  Google Scholar 

  20. Taylor CT, Furuta GT, Synnestvedt K, Colgan SP: Phosphorylation-dependent targeting of cAMP response element binding protein to the ubiquitin/proteasome pathway in hypoxia. Proc Natl Acad Sci USA 97: 12091–12096, 2000

    PubMed  Google Scholar 

  21. Schmedtje JF Jr., Ji YS, Liu WL, DuBois RN, Runge MS: Hypoxia induces cyclooxygenase-2 via the NF-kappaB p65 transcription factor in human vascular endothelial cells. J Biol Chem 272: 601–608, 1997

    PubMed  Google Scholar 

  22. Faller DV: Endothelial cell responses to hypoxic stress. Clin Exp Pharmacol Physiol 26: 74–84, 1999

    PubMed  Google Scholar 

  23. Yan SF, Lu J, Zou YS, Soh-Won J, Cohen DM, Buttrick PM, Cooper DR, Steinberg SF, Mackman N, Pinsky DJ, Stern DM: Hypoxia-associated induction of early growth response-1 gene expression. J Biol Chem 274: 15030–15040, 1999

    PubMed  Google Scholar 

  24. Koong AC, Giaccia AJ: Hypoxia-mediated signaling pathways (Chapter 311). In Handbook of Cell Signaling. Bradshaw RA, Dennis EA, eds. Elsevier Science, 2003, pp. 277–281

  25. Koong AC, Denko NC, Hudson KM, Schindler C, Swiersz L, Koch C, Evans S, Ibrahim H, Le QT, Terris DJ, Giaccia AJ: Candidate genes for the hypoxic tumor phenotype. Cancer Res 60: 883–887, 2000

    PubMed  Google Scholar 

  26. Wykoff CC, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ: Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumor suppressor by mRNA differential expression profiling. Oncogene 19: 6297–6305, 2000

    PubMed  Google Scholar 

  27. Denko NC, Fontana LA, Hudson KM, Sutphin PD, Altman SR, Giaccia AJ: Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 22: 5907–5914, 2003

    PubMed  Google Scholar 

  28. Scandurro AB, Weldon CW, Figueroa YG, Alam J, Beckman BS: Gene microarray analysis reveals a novel hypoxia signal transduction pathway in human hepatocellular carcinoma cells. Int J Oncol 19: 129–135, 2001

    PubMed  Google Scholar 

  29. Kunz M, Moeller S, Koczan D, Lorenz P, Wenger RH, Glocker MO, Thiesen HJ, Gross G, Ibrahim SM: Mechanisms of hypoxic gene regulation of angiogenesis factor Cyr61 in melanoma cells. J Biol Chem 278: 45651–45660, 2003

    PubMed  Google Scholar 

  30. Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JH, van der Kogel AJ, Riggins GJ: Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 93: 1337–1343, 2001

    PubMed  Google Scholar 

  31. Yan SF, Zou YS, Gao Y, Zhai C, Mackman N, Lee SL, Milbrandt J, Pinsky D, Kisiel W, Stern D: Tissue factor transcription driven by Egr-1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia. Proc Natl Acad Sci USA 95: 8298–8303, 1998

    PubMed  Google Scholar 

  32. Postovit LM, Adams MA, Lash GE, Heaton JP, Graham CH: Oxygen-mediated regulation of tumor cell invasiveness. Involvement of a nitric oxide signaling pathway. J Biol Chem 277: 35730–35737, 2002

    PubMed  Google Scholar 

  33. Harbeck N, Kates RE, Look MP, Meijer-van Gelder ME, Klijn JG, Kruger A, Kiechle M, Janicke F, Schmitt M, Foekens JA: Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3,424). Cancer Res 62: 4617–4622, 2002

    PubMed  Google Scholar 

  34. Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O'Higgins N, Eppenberger U, Janicke F, Schmitt M, Foekens JA: Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8,377 breast cancer patients. J Natl Cancer Inst 94: 116–128, 2002

    PubMed  Google Scholar 

  35. Janicke F, Schmitt M, Ulm K, Gossner W, Graeff H: Urokinase-type plasminogen activator antigen and early relapse in breast cancer. Lancet 2: 1049, 1989

    PubMed  Google Scholar 

  36. Janicke F, Pache L, Schmitt M, Ulm K, Thomssen C, Prechtl A, Graeff H: Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1. Cancer Res 54: 2527–2530, 1994

    PubMed  Google Scholar 

  37. Dunbar SD, Ornstein DL, Zacharski LR: Cancer treatment with inhibitors of urokinase-type plasminogen activator and plasmin. Expert Opin Investig Drugs 9: 2085–2092, 2000

    PubMed  Google Scholar 

  38. Uetsuji S, Yamamura M, Takai S, Hioki K, Yamamoto M: Effect of aprotinin on metastasis of Lewis lung tumor in mice. Surg Today 22: 439–442, 1992

    PubMed  Google Scholar 

  39. Monden T, Morimoto H, Shimano T, Yagyu T, Murotani M, Nagaoka H, Kawasaki Y, Kobayashi T, Mori T: Use of fibrinogen to enhance the antitumor effect of OK-432. A new approach to immunotherapy for colorectal carcinoma. Cancer 69: 636–642, 1992

    PubMed  Google Scholar 

  40. Lentschener C, Benhamou D, Mercier FJ, Boyer-Neumann C, Naveau S, Smadja C, Wolf M, Franco D: Aprotinin reduces blood loss in patients undergoing elective liver resection. Anesth Analg 84: 875–881, 1997

    PubMed  Google Scholar 

  41. Putnam JB, Royston D: Evaluating the role of serine protease inhibition in the management of tumor micrometastases. Oncology (Huntingt) 17: 9–30; quiz 31-32, 2003

    Google Scholar 

  42. Weber GF: The metastasis gene osteopontin: A candidate target for cancer therapy. Biochim Biophys Acta 1552: 61–85, 2001

    PubMed  Google Scholar 

  43. Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BL: Altered wound healing in mice lacking a functional osteopontin gene (spp1). J Clin Invest 101: 1468–1478, 1998

    Google Scholar 

  44. Le QT, Sutphin PD, Raychaudhuri S, Yu SC, Terris DJ, Lin HS, Lum B, Pinto HA, Koong AC, Giaccia AJ: Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas. Clin Cancer Res 9: 59–67, 2003

    PubMed  Google Scholar 

  45. Overgaard J, Nordsmark M, Alsner J, Eriksen JG, Nielsen TB, Lukacova S, Horsman MR: Plasma osteopontin (OPN) predicts hypoxia and response to the hypoxic sensitizer Nimorazole in radiotherapy of head and neck cancer. Results from the randomized DAHANCA 5 trial (poster # 474), European Society of Therapeutic Radiology and Oncology, 2003

  46. Singhal H, Bautista DS, Tonkin KS, O'Malley FP, Tuck AB, Chambers AF, Harris JF: Elevated plasma osteopontin in metastatic breast cancer associated with increased tumor burden and decreased survival. Clin Cancer Res 3: 605–611, 1997

    PubMed  Google Scholar 

  47. Tuck AB, O'Malley FP, Singhal H, Harris JF, Tonkin KS, Kerkvliet N, Saad Z, Doig GS, Chambers AF: Osteopontin expression in a group of lymph node negative breast cancer patients. Int J Cancer 79: 502–508, 1998

    PubMed  Google Scholar 

  48. Ue T, Yokozaki H, Kitadai Y, Yamamoto S, Yasui W, Ishikawa T, Tahara E: Co-expression of osteopontin and CD44v9 in gastric cancer. Int J Cancer 79: 127–132, 1998

    PubMed  Google Scholar 

  49. Saitoh Y, Kuratsu J, Takeshima H, Yamamoto S, Ushio Y: Expression of osteopontin in human glioma. Its correlation with the malignancy. Lab Invest 72: 55–63, 1995

    PubMed  Google Scholar 

  50. Agrawal D, Chen T, Irby R, Quackenbush J, Chambers AF, Szabo M, Cantor A, Coppola D, Yeatman TJ: Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling. J Natl Cancer Inst 94: 513–521, 2002

    PubMed  Google Scholar 

  51. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 9: 416–423, 2003

    PubMed  Google Scholar 

  52. Pan HW, Ou YH, Peng SY, Liu SH, Lai PL, Lee PH, Sheu JC, Chen CL, Hsu HC: Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer 98: 119–127, 2003

    PubMed  Google Scholar 

  53. Denhardt DT, Guo X: Osteopontin: A protein with diverse functions. Faseb J 7: 1475–1482, 1993

    PubMed  Google Scholar 

  54. Behrend EI, Craig AM, Wilson SM, Denhardt DT, Chambers AF: Expression of antisense osteopontin RNA in metastatic mouse fibroblasts is associated with reduced malignancy. Ann N Y Acad Sci 760: 299–301, 1995

    PubMed  Google Scholar 

  55. Wu Y, Denhardt DT, Rittling SR: Osteopontin is required for full expression of the transformed phenotype by the ras oncogene. Br J Cancer 83: 156–163, 2000

    PubMed  Google Scholar 

  56. Crawford HC, Matrisian LM, Liaw L: Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Res 58: 5206–5215, 1998

    PubMed  Google Scholar 

  57. Horuk R: Chemokine receptors. Cytokine Growth Factor Rev 12: 313–335, 2001

    PubMed  Google Scholar 

  58. Murphy PM: Chemokines and the molecular basis of cancer metastasis. N Engl J Med 345: 833–835, 2001

    PubMed  Google Scholar 

  59. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature 410: 50–56, 2001

    PubMed  Google Scholar 

  60. Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK: Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res 62: 1832–1837, 2002

    PubMed  Google Scholar 

  61. Robledo MM, Bartolome RA, Longo N, Rodriguez-Frade JM, Mellado M, Longo I, van Muijen GN, Sanchez-Mateos P, Teixido J: Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. J Biol Chem 276: 45098–45105, 2001

    PubMed  Google Scholar 

  62. Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP, Ben-Baruch A: A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol 167: 4747–4757, 2001

    PubMed  Google Scholar 

  63. Burger M, Glodek A, Hartmann T, Schmitt-Graff A, Silberstein LE, Fujii N, Kipps TJ, Burger JA: Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells. Oncogene 22: 8093–8101, 2003

    PubMed  Google Scholar 

  64. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J: A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3: 537–549, 2003

    PubMed  Google Scholar 

  65. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W: Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumor suppressor pVHL. Nature 425: 307–311, 2003

    PubMed  Google Scholar 

  66. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR: Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393: 595–599, 1998

    PubMed  Google Scholar 

  67. Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y, Kitamura Y, Matsushima K, Yoshida N, Nishikawa S, Kishimoto T, Nagasawa T: The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393: 591–594, 1998

    PubMed  Google Scholar 

  68. Tamamura H, Xu Y, Hattori T, Zhang X, Arakaki R, Kanbara K, Omagari A, Otaka A, Ibuka T, Yamamoto N, Nakashima H, Fujii N: A low-molecular-weight inhibitor against the chemokine receptor CXCR4: A strong anti-HIV peptide T140. Biochem Biophys Res Commun 253: 877–882, 1998

    PubMed  Google Scholar 

  69. Tamamura H, Murakami T, Masuda M, Otaka A, Takada W, Ibuka T, Nakashima H, Waki M, Matsumoto A, Yamamoto N, et al.: Structure-activity relationships of an anti-HIV peptide, T22. Biochem Biophys Res Commun 205: 1729–1735, 1994

    PubMed  Google Scholar 

  70. Doranz BJ, Grovit-Ferbas K, Sharron MP, Mao SH, Goetz MB, Daar ES, Doms RW, O'Brien WA: A smallmolecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor. J Exp Med 186: 1395–1400, 1997

    PubMed  Google Scholar 

  71. Schols D, Struyf S, Van Damme J, Este JA, Henson G, De Clercq E: Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J Exp Med 186: 1383–1388, 1997

    PubMed  Google Scholar 

  72. Trusolino L, Comoglio PM: Scatter-factor and semaphorin receptors: Cell signaling for invasive growth. Nat Rev Cancer 2: 289–300, 2002

    PubMed  Google Scholar 

  73. Nakamura T, Teramoto H, Ichihara A: Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures. Proc Natl Acad Sci USA 83: 6489–6493, 1986

    PubMed  Google Scholar 

  74. Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N: Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373: 702–705, 1995

    PubMed  Google Scholar 

  75. Takayama H, La Rochelle WJ, Anver M, Bockman DE, Merlino G: Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development. Proc Natl Acad Sci USA 93: 5866–5871, 1996

    PubMed  Google Scholar 

  76. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C: Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373: 699–702, 1995

    PubMed  Google Scholar 

  77. Miyazawa K, Shimomura T, Naka D, Kitamura N: Proteolytic activation of hepatocyte growth factor in response to tissue injury. J Biol Chem 269: 8966–8970, 1994

    PubMed  Google Scholar 

  78. Yanagita K, Matsumoto K, Sekiguchi K, Ishibashi H, Niho Y, Nakamura T: Hepatocyte growth factor may act as a pulmotrophic factor on lung regeneration after acute lung injury. J Biol Chem 268: 21212–21217, 1993

    PubMed  Google Scholar 

  79. Vande Woude GF, Jeffers M, Cortner J, Alvord G, Tsarfaty I, Resau J: Met-HGF/SF: Tumorigenesis, invasion and metastasis. Ciba Found Symp 212: 119–130; discussion 130-112, 148-154, 1997

    PubMed  Google Scholar 

  80. Comoglio PM, Trusolino L: Invasive growth: From development to metastasis. J Clin Invest 109: 857–862, 2002

    PubMed  Google Scholar 

  81. Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M, Lubensky I, Neumann HP, Brauch H, Decker J, Vocke C, Brown JA, Jenkins R, Richard S, Bergerheim U, Gerrard B, Dean M, Linehan WM, Zbar B: Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18: 2343–2350, 1999

    PubMed  Google Scholar 

  82. Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, Valente G, Giordano S, Cortesina G, Comoglio PM: Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19: 1547–1555, 2000

    PubMed  Google Scholar 

  83. Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, Nordlinger B, Bretti S, Bottardi S, Giordano S, et al.: Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res 1: 147–154, 1995

    PubMed  Google Scholar 

  84. Di Renzo MF, Olivero M, Serini G, Orlandi F, Pilotti S, Belfiore A, Costantino A, Vigneri R, Angeli A, Pierotti MA, et al.: Overexpression of the c-MET/HGF receptor in human thyroid carcinomas derived from the follicular epithelium. J Endocrinol Invest 18: 134–139, 1995

    PubMed  Google Scholar 

  85. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM: Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3: 347–361, 2003

    PubMed  Google Scholar 

  86. Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C: K252a inhibits the oncogenic properties of Met, the HGF receptor. Oncogene 21: 4885–4893, 2002

    PubMed  Google Scholar 

  87. Bardelli A, Longati P, Williams TA, Benvenuti S, Comoglio PM: A peptide representing the carboxylterminal tail of the met receptor inhibits kinase activity and invasive growth. J Biol Chem 274: 29274–29281, 1999

    PubMed  Google Scholar 

  88. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J: Vascular-specific growth factors and blood vessel formation. Nature 407: 242–248, 2000

    PubMed  Google Scholar 

  89. Dvorak HF, Nagy JA, Feng D, Brown LF, Dvorak AM: Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol 237: 97–132, 1999

    PubMed  Google Scholar 

  90. Eriksson U, Alitalo K: Structure, expression and receptorbinding properties of novel vascular endothelial growth factors. Curr Top Microbiol Immunol 237: 41–57, 1999

    PubMed  Google Scholar 

  91. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. Faseb J 13: 9–22, 1999

    PubMed  Google Scholar 

  92. Tallquist MD, Soriano P, Klinghoffer RA: Growth factor signaling pathways in vascular development. Oncogene 18: 7917–7932, 1999

    PubMed  Google Scholar 

  93. Gale NW, Yancopoulos GD: Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 13: 1055–1066, 1999

    PubMed  Google Scholar 

  94. Carmeliet P, Collen D: Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development. Curr Top Microbiol Immunol 237: 133–158, 1999

    PubMed  Google Scholar 

  95. Cheng N, Brantley DM, Chen J: The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 13: 75–85, 2002

    PubMed  Google Scholar 

  96. Bruckner K, Pasquale EB, Klein R: Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 275: 1640–1643, 1997

    PubMed  Google Scholar 

  97. Holland SJ, Gale NW, Mbamalu G, Yancopoulos GD, Henkemeyer M, Pawson T: Bidirectional signaling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 383: 722–725, 1996

    PubMed  Google Scholar 

  98. Lin D, Gish GD, Songyang Z, Pawson T: The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif. J Biol Chem 274: 3726–3733, 1999

    PubMed  Google Scholar 

  99. Torres R, Firestein BL, Dong H, Staudinger J, Olson EN, Huganir RL, Bredt DS, Gale NW, Yancopoulos GD: PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21: 1453–1463, 1998

    PubMed  Google Scholar 

  100. Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R: Roles of ephrinB ligands and EphB receptors in cardiovascular development: Demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13: 295–306, 1999

    PubMed  Google Scholar 

  101. Gerety SS, Wang HU, Chen ZF, Anderson DJ: Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 4: 403–414, 1999

    PubMed  Google Scholar 

  102. Wang HU, Chen ZF, Anderson DJ: Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93: 741–753, 1998

    PubMed  Google Scholar 

  103. Holzman LB, Marks RM, Dixit VM: A novel immediateearly response gene of endothelium is induced by cytokines and encodes a secreted protein. Mol Cell Biol 10: 5830–5838, 1990

    PubMed  Google Scholar 

  104. McBride JL, Ruiz JC: Ephrin-A1 is expressed at sites of vascular development in the mouse. Mech Dev 77: 201–204, 1998

    PubMed  Google Scholar 

  105. Myers C, Charboneau A, Boudreau N: Homeobox B3 promotes capillary morphogenesis and angiogenesis. J Cell Biol 148: 343–351, 2000

    PubMed  Google Scholar 

  106. Pandey A, Shao H, Marks RM, Polverini PJ, Dixit VM: Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis. Science 268: 567–569, 1995

    PubMed  Google Scholar 

  107. Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F: A novel putative tyrosine kinase receptor encoded by the eph gene. Science 238: 1717–1720, 1987

    PubMed  Google Scholar 

  108. Maru Y, Hirai H, Yoshida MC, Takaku F: Evolution, expression, and chromosomal location of a novel receptor tyrosine kinase gene, eph. Mol Cell Biol 8: 3770–3776, 1988

    PubMed  Google Scholar 

  109. Maru Y, Hirai H, Takaku F: Overexpression confers an oncogenic potential upon the eph gene. Oncogene 5: 445–447, 1990

    PubMed  Google Scholar 

  110. Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL, Pasquale EB: The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19: 6043–6052, 2000

    PubMed  Google Scholar 

  111. Brantley DM, Cheng N, Thompson EJ, Lin Q, Brekken RA, Thorpe PE, Muraoka RS, Cerretti DP, Pozzi A, Jackson D, Lin C, Chen J: Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21: 7011–7026, 2002

    PubMed  Google Scholar 

  112. Cheng N, Brantley DM, Liu H, Lin Q, Enriquez M, Gale N, Yancopoulos G, Cerretti DP, Daniel TO, Chen J: Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol Cancer Res 1: 2–11, 2002

    PubMed  Google Scholar 

  113. Alarcon RM, Denko NC, Giaccia AJ: Genetic determinants that influence hypoxia-induced apoptosis. In Causes and Consequences of Acidic pH in tumors. Goode J, ed. London, England, Novartis Found Symp, 2001, pp. 115–128

  114. Maecker H, Yun Z, Giaccia A: Epigenetic changes in tumor Fas levels determine immune escape and response to therapy. Cancer Cell 2: 139, 2002

    PubMed  Google Scholar 

  115. Azhar G, Liu L, Zhang X, Wei JY: Influence of age on hypoxia/reoxygenation-induced DNA fragmentation and bcl-2, bcl-xl, bax and fas in the rat heart and brain. Mech aging Dev 112: 5–25, 1999

    PubMed  Google Scholar 

  116. Saikumar P, Dong Z, Patel Y, Hall K, Hopfer U, Weinberg JM, Venkatachalam MA: Role of hypoxiainduced Bax translocation and cytochrome c release in reoxygenation injury. Oncogene 17: 3401–3415, 1998

    PubMed  Google Scholar 

  117. Stempien-Otero A, Karsan A, Cornejo CJ, Xiang H, Eunson T, Morrison RS, Kay M, Winn R, Harlan J: Mechanisms of hypoxia-induced endothelial cell death. Role of p53 in apoptosis. J Biol Chem 274: 8039–8045, 1999

    PubMed  Google Scholar 

  118. Tamatani M, Mitsuda N, Matsuzaki H, Okado H, Miyake S, Vitek MP, Yamaguchi A, Tohyama M: A pathway of neuronal apoptosis induced by hypoxia/ reoxygenation: Roles of nuclear factor-kappaB and Bcl-2. J Neurochem 75: 683–693, 2000

    PubMed  Google Scholar 

  119. Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L: PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci USA 100: 1931–1936, 2003

    PubMed  Google Scholar 

  120. Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ, Adams JM, Strasser A: p53-and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302: 1036–1038, 2003

    PubMed  Google Scholar 

  121. Koumenis C, Alarcon R, Hammond E, Sutphin P, Hoffman W, Murphy M, Derr J, Taya Y, Lowe SW, Kastan M, Giaccia A: Regulation of p53 by hypoxia: Dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Mol Cell Biol 21: 1297–1310, 2001

    PubMed  Google Scholar 

  122. Bruick RK: Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 97: 9082–9087, 2000

    PubMed  Google Scholar 

  123. Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH: BH3-only Protein Noxa Is a Mediator of Hypoxic Cell Death Induced by Hypoxia-inducible Factor 1?. J Exp Med 199: 113–124, 2004

    PubMed  Google Scholar 

  124. Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, Gietz RD, Greenberg AH: BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites. J Biol Chem 275: 1439–1448, 2000

    PubMed  Google Scholar 

  125. Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R, Greenberg AH: BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 20: 5454–5468, 2000

    PubMed  Google Scholar 

  126. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors. Nature 379: 88–91, 1996

    PubMed  Google Scholar 

  127. Maxwell SA, Davis GE: Differential gene expression in p53-mediated apoptosis-resistant vs. apoptosis-sensitive tumor cell lines. Proc Natl Acad Sci USA 97: 13009–13014, 2000

    PubMed  Google Scholar 

  128. Vousden KH: p53: Death star. Cell 103: 691–694, 2000

    PubMed  Google Scholar 

  129. Semenza GL, Roth PH, Fang H-M, Wang GL: Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269: 23757–23767, 1994

    PubMed  Google Scholar 

  130. Ebert BL, Gleadle JM, O'Rourke JF, Bartlett SM, Poulton J, Ratcliffe PJ: Isoenzyme-specific regulation of genes involved in energy metabolism by hypoxia: Similarities with the regulation of erythropoietin. Biochem J 313(Pt 3): 809–814, 1996

    PubMed  Google Scholar 

  131. Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A: Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271: 32529–32537, 1996

    PubMed  Google Scholar 

  132. Ebert BL, Firth JD, Ratcliffe PJ: Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J Biol Chem 270: 29083–29089, 1995

    PubMed  Google Scholar 

  133. O'Rourke JF, Pugh CW, Bartlett SM, Ratcliffe PJ: Identification of hypoxically inducible mRNAs in HeLa cells using differential-display PCR. Role of hypoxiainducible factor-1. Eur J Biochem 241: 403–410, 1996

    PubMed  Google Scholar 

  134. Graven KK, McDonald RJ, Farber HW: Hypoxic regulation of endothelial glyceraldehyde-3-phosphate dehydrogenase. Am J Physiol 274: C347–355, 1998

    PubMed  Google Scholar 

  135. Riddle SR, Ahmad A, Ahmad S, Deeb SS, Malkki M, Schneider BK, Allen CB, White CW: Hypoxia induces hexokinase II gene expression in human lung cell line A549. Am J Physiol Lung Cell Mol Physiol 278: L407–416, 2000

    PubMed  Google Scholar 

  136. Salceda S, Beck I, Caro J: Absolute requirement of aryl hydrocarbon receptor nuclear translocator protein for gene activation by hypoxia. Arch Biochem Biophys 334: 389–394, 1996

    PubMed  Google Scholar 

  137. Leonard MO, Cottell DC, Godson C, Brady HR, Taylor CT: The role of HIF-1 alpha in transcriptional regulation of the proximal tubular epithelial cell response to hypoxia. J Biol Chem 278: 40296–40304, 2003

    PubMed  Google Scholar 

  138. Discher DJ, Bishopric NH, Wu X, Peterson CA, Webster KA: Hypoxia regulates beta-enolase and pyruvate kinase-M promoters by modulating Sp1/Sp3 binding to a conserved GC element. J Biol Chem 273: 26087–26093, 1998

    PubMed  Google Scholar 

  139. Denko N, Schindler C, Koong A, Laderoute K, Green C, Giaccia A: Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment. Clin Cancer Res 6: 480–487, 2000

    PubMed  Google Scholar 

  140. Niitsu Y, Hori O, Yamaguchi A, Bando Y, Ozawa K, Tamatani M, Ogawa S, Tohyama M: Exposure of cultured primary rat astrocytes to hypoxia results in intracellular glucose depletion and induction of glycolytic enzymes. Brain Res Mol Brain Res 74: 26–34, 1999

    PubMed  Google Scholar 

  141. Kawaguchi T, Veech RL, Uyeda K: Regulation of energy metabolism in macrophages during hypoxia. Roles of fructose 2,6-bisphosphate and ribose 1,5-bisphosphate. J Biol Chem 276: 28554–28561, 2001

    PubMed  Google Scholar 

  142. Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, Zavada J, Waheed A, Sly W, Lerman MI, Stanbridge EJ: Expression of hypoxia-inducible cellsurface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158: 905–919, 2001

    PubMed  Google Scholar 

  143. Mukhopadhyay CK, Mazumder B, Fox PL: Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem 275: 21048–21054, 2000

    PubMed  Google Scholar 

  144. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE: Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the erythropoietin gene. Proc Natl Acad Sci USA 88: 5680–5684, 1991

    PubMed  Google Scholar 

  145. Smith JJ, O'Brien-Ladner AR, Kaiser CR, Wesselius LJ: Effects of hypoxia and nitric oxide on ferritin content of alveolar cells. J Lab Clin Med 141: 309–317, 2003

    PubMed  Google Scholar 

  146. Yang ZZ, Zou AP: Transcriptional regulation of heme oxygenases by HIF-1? in renal medullary interstitial cells. Am J Physiol Renal Physiol 281: F900–908, 2001

    PubMed  Google Scholar 

  147. Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G: Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific posttranscriptional regulation. J Biol Chem 274: 24142–24146, 1999

    PubMed  Google Scholar 

  148. Enholm B, Paavonen K, Ristimaki A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U, Alitalo K: Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14: 2475–2483, 1997

    PubMed  Google Scholar 

  149. Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843–845, 1992

    PubMed  Google Scholar 

  150. Plate KH, Breier G, Millauer B, Ullrich A, Risau W: Upregulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Research 53: 5822–5827, 1993

    PubMed  Google Scholar 

  151. Gleadle JM, Ebert BL, Firth JD, Ratcliffe PJ: Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. Am J Physiol 268: C1362–1368, 1995

    PubMed  Google Scholar 

  152. Mandriota SJ, Pepper MS: Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res 83: 852–859, 1998

    PubMed  Google Scholar 

  153. Kourembanas S, McQuillan LP, Leung GK, Faller DV: Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 92: 99–104, 1993

    PubMed  Google Scholar 

  154. Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L: A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promotor. J Exp Med 182: 1683–1693, 1995

    PubMed  Google Scholar 

  155. Tenan M, Fulci G, Albertoni M, Diserens AC, Hamou MF, El Ati.-Borel M, Feige JJ, Pepper MS, Van Meir EG: Thrombospondin-1 is downregulated by anoxia and suppresses tumorigenicity of human glioblastoma cells. J Exp Med 191: 1789–1798, 2000

    PubMed  Google Scholar 

  156. Vasir B, Reitz P, Xu G, Sharma A, Bonner-Weir S, Weir GC: Effects of diabetes and hypoxia on gene markers of angiogenesis (HGF, cMET, uPA and uPAR, TGF-alpha, TGF-beta, bFGF and Vimentin) in cultured and transplanted rat islets. Diabetologia 43: 763–772, 2000

    PubMed  Google Scholar 

  157. Schaffer L, Scheid A, Spielmann P, Breymann C, Zimmermann R, Meuli M, Gassmann M, Marti HH, Wenger RH: Oxygen-regulated expression of TGF-beta 3, a growth factor involved in trophoblast differentiation. Placenta 24: 941–950, 2003

    PubMed  Google Scholar 

  158. Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, Semenza GL: Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63: 1138–1143, 2003

    PubMed  Google Scholar 

  159. Willam C, Koehne P, Jurgensen JS, Grafe M, Wagner KD, Bachmann S, Frei U, Eckardt KU: Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells. Circ Res 87: 370–377, 2000

    PubMed  Google Scholar 

  160. Grilli A, De Lutiis MA, Patruno A, Speranza L, Cataldi A, Centurione L, Taccardi AA, Di Napoli P, De Caterina R, Barbacane R, Conti P, Felaco M: Effect of chronic hypoxia on inducible nitric oxide synthase expression in rat myocardial tissue. Exp Biol Med (Maywood) 228: 935–942, 2003

    Google Scholar 

  161. Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, Lewis CE: Hypoxia-induced gene expression in human macrophages: Implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 163: 1233–1243, 2003

    PubMed  Google Scholar 

  162. Suzuma K, Takagi H, Otani A, Honda Y: Hypoxia and vascular endothelial growth factor stimulate angiogenic integrin expression in bovine retinal microvascular endothelial cells. Invest Ophthalmol Vis Sci 39: 1028–1035, 1998

    PubMed  Google Scholar 

  163. Pinsky DJ, Liao H, Lawson CA, Yan SF, Chen J, Carmeliet P, Loskutoff DJ, Stern DM: Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 102: 919–928, 1998

    PubMed  Google Scholar 

  164. Graham CH, Fitzpatrick TE, McCrae KR: Hypoxia stimulates urokinase receptor expression through a heme-dependent pathway. Blood 91: 3300–3307, 1998

    PubMed  Google Scholar 

  165. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ: C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: 43–54, 2001

    PubMed  Google Scholar 

  166. Tazuke SI, Mazure NM, Sugawara J, Carland G, Faessen GH, Suen LF, Irwin JC, Powell DR, Giaccia AJ, Giudice LC: Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HepG2 cells: A possible model for IGFBP-1 expression in fetal hypoxia. Proc Natl Acad Sci USA 95: 10188–10193, 1998

    PubMed  Google Scholar 

  167. Ozawa K, Tsukamoto Y, Hori O, Kitao Y, Yanagi H, Stern DM, Ogawa S: Regulation of tumor angiogenesis by oxygen-regulated protein 150, an inducible endoplasmic reticulum chaperone. Cancer Res 61: 4206–4213, 2001

    PubMed  Google Scholar 

  168. Roll DE, Murphy BJ, Laderoute KR, Sutherland RM, Smith HC: Oxygen regulated 80 kDa protein and glucose regulated 78 kDa protein are identical. Mol Cell Biochem 103: 141–148, 1991

    PubMed  Google Scholar 

  169. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E: Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis. Nature 394: 485–490, 1998

    PubMed  Google Scholar 

  170. Kraggerud SM, Sandvik JA, Pettersen EO: Regulation of protein synthesis in human cells exposed to extreme hypoxia. Anticancer Res 15: 683–686, 1995

    PubMed  Google Scholar 

  171. Aaronson RM, Graven KK, Tucci M, McDonald RJ, Farber HW: Non-neuronal enolase is an endothelial hypoxic stress protein. J Biol Chem 270: 27752–27757, 1995

    PubMed  Google Scholar 

  172. Baek SH, Lee UY, Park EM, Han MY, Lee YS, Park YM: Role of protein kinase Cdelta in transmitting hypoxia signal to HSF and HIF-1. J Cell Physiol 188: 223–235, 2001

    PubMed  Google Scholar 

  173. Saarikoski ST, Rivera SP, Hankinson O: Mitogeninducible gene 6 (MIG-6), adipophilin and tuftelin are inducible by hypoxia. FEBS Lett 530: 186–190, 2002

    PubMed  Google Scholar 

  174. Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM: Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 13: 64–75, 1999

    PubMed  Google Scholar 

  175. Oikawa M, Abe M, Kurosawa H, Hida W, Shirato K, Sato Y: Hypoxia induces transcription factor ETS-1 via the activity of hypoxia-inducible factor-1. Biochem Biophys Res Commun 289: 39–43, 2001

    PubMed  Google Scholar 

  176. Muller JM, Krauss B, Kaltschmidt C, Baeuerle PA, Rupec RA: Hypoxia induces c-fos transcription via a mitogenactivated protein kinase-dependent pathway. J Biol Chem 272: 23435–23439, 1997

    PubMed  Google Scholar 

  177. Ausserer WA, Bourrat-Floeck B, Green CJ, Laderoute KR, Sutherland RM: Regulation of c-jun expression during hypoxic and low-glucose stress. Mol Cell Biol 14: 5032–5042, 1994

    PubMed  Google Scholar 

  178. Koong AC, Chen EY, Giaccia AJ: Hypoxia causes the activation of nuclear factor kappa B through the phosphorylation of I kappa B alpha on tyrosine residues. Cancer Res 54: 1425–1430, 1994

    PubMed  Google Scholar 

  179. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL: HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61: 6669–6673, 2001

    PubMed  Google Scholar 

  180. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL: Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59: 3915–3918, 1999

    PubMed  Google Scholar 

  181. Matsui H, Ihara Y, Fujio Y, Kunisada K, Akira S, Kishimoto T, Yamauchi-Takihara K: Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kappa B and NF-IL6 in cardiac myocytes. Cardiovasc Res 42: 104–112, 1999

    PubMed  Google Scholar 

  182. Berger AP, Kofler K, Bektic J, Rogatsch H, Steiner H, Bartsch G, Klocker H: Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia. Prostate 57: 57–65, 2003

    PubMed  Google Scholar 

  183. Furuta GT, Turner JR., Taylor CT, Hershberg RM, Comerford K, Narravula S, Podolsky DK, Colgan SP: Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J Exp Med 193: 1027–1034, 2001

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cancer and Radiation Biology, Stanford University School of Medicine, Department of Radiation Oncology, CCSR – South, Room 1255, 269 Campus Drive, Stanford, CA, 94305-5152

    Quynh-Thu Le, Nicholas C. Denko & Amato J. Giaccia

Authors
  1. Quynh-Thu Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas C. Denko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amato J. Giaccia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amato J. Giaccia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Le, QT., Denko, N.C. & Giaccia, A.J. Hypoxic gene expression and metastasis. Cancer Metastasis Rev 23, 293–310 (2004). https://doi.org/10.1023/B:CANC.0000031768.89246.d7

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:CANC.0000031768.89246.d7

Search

Navigation