© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 17, 1337-1343,
September 5, 2001
© 2001 Oxford University Press
REPORT |
Transcriptional Response to Hypoxia in Human Tumors
Affiliations of authors: A. Lal (Department of Pathology), Z. A. Haroon, M. W. Dewhirst (Department of Radiation Oncology), G. J. Riggins (Departments of Pathology and Genetics), Duke University Medical Center, Durham, NC; H. Peters, J. H. A. M. Kaanders, A. J. van der Kogel, Institute of Radiotherapy, University of Nijmegen, The Netherlands; B. St. Croix, The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, MD; R. L. Strausberg, Cancer Genomics Office, Office of the Director, National Cancer Institute, Bethesda, MD.
Correspondence to:Gregory J. Riggins, M.D., Ph.D., Cancer Genomics Laboratory, Duke University Medical Center, Box 3156, Durham, NC 27710 (e-mail: greg.riggins{at}duke.edu).
Background: The presence of hypoxic regions within solid tumors is associated with a more malignant tumor phenotype and worse prognosis. To obtain a blood supply and protect against cellular damage and death, oxygen-deprived cells in tumors alter gene expression, resulting in resistance to therapy. To investigate the mechanisms by which cancer cells adapt to hypoxia, we looked for novel hypoxia-induced genes. Methods: The transcriptional response to hypoxia in human glioblastoma cells was quantified with the use of serial analysis of gene expression. The time course of gene expression in response to hypoxia in a panel of various human tumor cell lines was measured by real-time polymerase chain reaction. Hypoxic regions of human carcinomas were chemically marked with pimonidazole. Immunohistochemistry and in situ hybridization were used to examine gene expression in the tumor's hypoxic regions. Results: From the 24 504 unique transcripts expressed, 10 new hypoxia-regulated genes were detected—all induced, to a greater extent than vascular endothelial growth factor, a hypoxia-induced mitogen that promotes blood vessel growth. These genes also responded to hypoxia in breast and colon cancer cells and were activated by hypoxia-inducible factor 1, a key regulator of hypoxic responses. In tumors, gene expression was limited to hypoxic regions. Induced genes included hexabrachion (an extracellular matrix glycoprotein), stanniocalcin 1 (a calcium homeostasis protein), and an angiopoietin-related gene. Conclusions: We have identified the genes that are transcriptionally activated within hypoxic malignant cells, a crucial first step in understanding the complex interactions driving hypoxia response. Within our catalogue of hypoxia-responsive genes are novel candidates for hypoxia-driven angiogenesis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. John-Aryankalayil, S. T. Palayoor, D. Cerna, M. T. Falduto, S. R. Magnuson, and C. N. Coleman NS-398, ibuprofen, and cyclooxygenase-2 RNA interference produce significantly different gene expression profiles in prostate cancer cells Mol. Cancer Ther., January 1, 2009; 8(1): 261 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C.-M. Chang, J. Hook, F. A. Lemckert, M. M. McDonald, M.-A. T. Nguyen, E. C. Hardeman, D. G. Little, P. W. Gunning, and R. R. Reddel The Murine Stanniocalcin 2 Gene Is a Negative Regulator of Postnatal Growth Endocrinology, May 1, 2008; 149(5): 2403 - 2410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Furuta, S. K. Pai, R. Zhan, S. Bandyopadhyay, M. Watabe, Y.-Y. Mo, S. Hirota, S. Hosobe, T. Tsukada, K. Miura, et al. Fatty Acid Synthase Gene Is Up-regulated by Hypoxia via Activation of Akt and Sterol Regulatory Element Binding Protein-1 Cancer Res., February 15, 2008; 68(4): 1003 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kaidi, M. Moorghen, A. C. Williams, and C. Paraskeva Is the downregulation of EphB2 receptor expression during colorectal tumorigenesis due to hypoxia? Gut, November 1, 2007; 56(11): 1637 - 1638. [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Moller-Levet, C. M. West, and C. J. Miller Exploiting sample variability to enhance multivariate analysis of microarray data Bioinformatics, October 15, 2007; 23(20): 2733 - 2740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Y. Tan, L. Campo, C. Han, H. Turley, F. Pezzella, K. C. Gatter, A. L. Harris, and S. B. Fox BNIP3 as a Progression Marker in Primary Human Breast Cancer; Opposing Functions in In situ Versus Invasive Cancer Clin. Cancer Res., January 15, 2007; 13(2): 467 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yoo, G. S. Baia, J. S. Smith, M. W. McDermott, A. W. Bollen, S. R. VandenBerg, K. R. Lamborn, and A. Lal Expression of the Hypoxia Marker Carbonic Anhydrase 9 Is Associated with Anaplastic Phenotypes in Meningiomas Clin. Cancer Res., January 1, 2007; 13(1): 68 - 75. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Galaup, A. Cazes, S. Le Jan, J. Philippe, E. Connault, E. Le Coz, H. Mekid, L. M. Mir, P. Opolon, P. Corvol, et al. Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness PNAS, December 5, 2006; 103(49): 18721 - 18726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Schweppe, T. H. Cheung, and N. G. Ahn Global Gene Expression Analysis of ERK5 and ERK1/2 Signaling Reveals a Role for HIF-1 in ERK5-mediated Responses J. Biol. Chem., July 28, 2006; 281(30): 20993 - 21003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Newbold, M Partridge, G Cook, S A Sohaib, E Charles-Edwards, P Rhys-Evans, K Harrington, and C Nutting Advanced imaging applied to radiotherapy planning in head and neck cancer: a clinical review. Br. J. Radiol., July 1, 2006; 79(943): 554 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q.-T. Le, G. Shi, H. Cao, D. W. Nelson, Y. Wang, E. Y. Chen, S. Zhao, C. Kong, D. Richardson, K. J. O'Byrne, et al. Galectin-1: A Link Between Tumor Hypoxia and Tumor Immune Privilege J. Clin. Oncol., December 10, 2005; 23(35): 8932 - 8941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Feldman, V. Chauhan, and A. C. Koong The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors Mol. Cancer Res., November 1, 2005; 3(11): 597 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Y. Yeung, K. P. Lai, H. Y. Chan, N. K. Mak, G. F. Wagner, and C. K. C. Wong Hypoxia-Inducible Factor-1-Mediated Activation of Stanniocalcin-1 in Human Cancer Cells Endocrinology, November 1, 2005; 146(11): 4951 - 4960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A.J. Kempf, M. Lebiedziejewski, K. Alitalo, J.-H. Walzlein, U. Ehehalt, J. Fiebig, S. Huber, B. Schutt, C. A. Sander, S. Muller, et al. Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis: Evidence for a Role of Hypoxia-Inducible Factor-1 in Bacterial Infections Circulation, March 1, 2005; 111(8): 1054 - 1062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Belbin, B. Singh, R. V. Smith, N. D. Socci, V. B. Wreesmann, M. Sanchez-Carbayo, J. Masterson, S. Patel, C. Cordon-Cardo, M. B. Prystowsky, et al. Molecular Profiling of Tumor Progression in Head and Neck Cancer Arch Otolaryngol Head Neck Surg, January 1, 2005; 131(1): 10 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Eisenhofer, T-T Huynh, K Pacak, F M Brouwers, M M Walther, W M Linehan, P J Munson, M Mannelli, D S Goldstein, and A G Elkahloun Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome Endocr. Relat. Cancer, December 1, 2004; 11(4): 897 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Kim, Z. N. Rabbani, R. T. Vollmer, E.-G. Schreiber, E. Oosterwijk, M. W. Dewhirst, Z. Vujaskovic, and M. J. Kelley Carbonic Anhydrase IX in Early-Stage Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2004; 10(23): 7925 - 7933. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Murdoch, A. Giannoudis, and C. E. Lewis Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues Blood, October 15, 2004; 104(8): 2224 - 2234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yamakawa, L. X. Liu, A. J. Belanger, T. Date, T. Kuriyama, M. A. Goldberg, S. H. Cheng, R. J. Gregory, and C. Jiang Expression of angiopoietins in renal epithelial and clear cell carcinoma cells: regulation by hypoxia and participation in angiogenesis Am J Physiol Renal Physiol, October 1, 2004; 287(4): F649 - F657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Francia, S. Man, B. Teicher, L. Grasso, and R. S. Kerbel Gene Expression Analysis of Tumor Spheroids Reveals a Role for Suppressed DNA Mismatch Repair in Multicellular Resistance to Alkylating Agents Mol. Cell. Biol., August 1, 2004; 24(15): 6837 - 6849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Streubel, A. Chott, D. Huber, M. Exner, U. Jager, O. Wagner, and I. Schwarzinger Lymphoma-Specific Genetic Aberrations in Microvascular Endothelial Cells in B-Cell Lymphomas N. Engl. J. Med., July 15, 2004; 351(3): 250 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Maseide, R. A. Kandel, R. S. Bell, C. N. Catton, B. O'Sullivan, J. S. Wunder, M. Pintilie, D. Hedley, and R. P. Hill Carbonic Anhydrase IX as a Marker for Poor Prognosis in Soft Tissue Sarcoma Clin. Cancer Res., July 1, 2004; 10(13): 4464 - 4471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Koike, N. Kimura, K. Miyazaki, T. Yabuta, K. Kumamoto, S. Takenoshita, J. Chen, M. Kobayashi, M. Hosokawa, A. Taniguchi, et al. Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates PNAS, May 25, 2004; 101(21): 8132 - 8137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Cairns and R. P. Hill Acute Hypoxia Enhances Spontaneous Lymph Node Metastasis in an Orthotopic Murine Model of Human Cervical Carcinoma Cancer Res., March 15, 2004; 64(6): 2054 - 2061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. A. LaRue, M. Khalil, and J. P. Freyer Microenvironmental Regulation of Proliferation in Multicellular Spheroids Is Mediated through Differential Expression of Cyclin-Dependent Kinase Inhibitors Cancer Res., March 1, 2004; 64(5): 1621 - 1631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Evans, K. D. Judy, I. Dunphy, W. T. Jenkins, P. T. Nelson, R. Collins, E. P. Wileyto, K. Jenkins, S. M. Hahn, C. W. Stevens, et al. Comparative Measurements of Hypoxia in Human Brain Tumors Using Needle Electrodes and EF5 Binding Cancer Res., March 1, 2004; 64(5): 1886 - 1892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. N. Coleman Linking Radiation Oncology and Imaging through Molecular Biology (or Now That Therapy and Diagnosis Have Separated, It's Time to Get Together Again!) Radiology, July 1, 2003; 228(1): 29 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bachtiary, M. Schindl, R. Potter, B. Dreier, T. H. Knocke, J. A. Hainfellner, R. Horvat, and P. Birner Overexpression of Hypoxia-inducible Factor 1{alpha} Indicates Diminished Response to Radiotherapy and Unfavorable Prognosis in Patients Receiving Radical Radiotherapy for Cervical Cancer Clin. Cancer Res., June 1, 2003; 9(6): 2234 - 2240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Le Jan, C. Amy, A. Cazes, C. Monnot, N. Lamande, J. Favier, J. Philippe, M. Sibony, J.-M. Gasc, P. Corvol, et al. Angiopoietin-Like 4 Is a Proangiogenic Factor Produced during Ischemia and in Conventional Renal Cell Carcinoma Am. J. Pathol., May 1, 2003; 162(5): 1521 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Brat and T. B. Mapstone Malignant Glioma Physiology: Cellular Response to Hypoxia and Its Role in Tumor Progression Ann Intern Med, April 15, 2003; 138(8): 659 - 668. [Full Text] [PDF]
|
|
|
|
|
|
K. Helczynska, A. Kronblad, A. Jogi, E. Nilsson, S. Beckman, G. Landberg, and S. Pahlman Hypoxia Promotes a Dedifferentiated Phenotype in Ductal Breast Carcinoma in Situ Cancer Res., April 1, 2003; 63(7): 1441 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Jiang, W. Zhang, K. Kondo, J. M. Klco, T. B. St. Martin, M. R. Dufault, S. L. Madden, W. G. Kaelin Jr, and M. Nacht Gene Expression Profiling in a Renal Cell Carcinoma Cell Line: Dissecting VHL and Hypoxia-Dependent Pathways Mol. Cancer Res., April 1, 2003; 1(6): 453 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Wascher, K. T. Huynh, A. E. Giuliano, N. M. Hansen, F. R. Singer, D. Elashoff, and D. S. B. Hoon Stanniocalcin-1: A Novel Molecular Blood and Bone Marrow Marker for Human Breast Cancer Clin. Cancer Res., April 1, 2003; 9(4): 1427 - 1435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. A. M. Kaanders, K. I. E. M. Wijffels, H. A. M. Marres, A. S. E. Ljungkvist, L. A. M. Pop, F. J. A. van den Hoogen, P. C. M. de Wilde, J. Bussink, J. A. Raleigh, and A. J. van der Kogel Pimonidazole Binding and Tumor Vascularity Predict for Treatment Outcome in Head and Neck Cancer Cancer Res., December 1, 2002; 62(23): 7066 - 7074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. McCudden, K. A. James, C. Hasilo, and G. F. Wagner Characterization of Mammalian Stanniocalcin Receptors. MITOCHONDRIAL TARGETING OF LIGAND AND RECEPTOR FOR REGULATION OF CELLULAR METABOLISM J. Biol. Chem., November 15, 2002; 277(47): 45249 - 45258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. H. Filvaroff, S. Guillet, C. Zlot, M. Bao, G. Ingle, H. Steinmetz, J. Hoeffel, S. Bunting, J. Ross, R. A. D. Carano, et al. Stanniocalcin 1 Alters Muscle and Bone Structure and Function in Transgenic Mice Endocrinology, September 1, 2002; 143(9): 3681 - 3690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Boon, E. C. Osorio, S. F. Greenhut, C. F. Schaefer, J. Shoemaker, K. Polyak, P. J. Morin, K. H. Buetow, R. L. Strausberg, S. J. de Souza, et al. An anatomy of normal and malignant gene expression PNAS, August 20, 2002; 99(17): 11287 - 11292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Watanabe, M. Ichihara, M. Hashimoto, K. Shimono, Y. Shimoyama, T. Nagasaka, Y. Murakumo, H. Murakami, H. Sugiura, H. Iwata, et al. Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation Am. J. Pathol., July 1, 2002; 161(1): 249 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lal, C. A. Glazer, H. M. Martinson, H. S. Friedman, G. E. Archer, J. H. Sampson, and G. J. Riggins Mutant Epidermal Growth Factor Receptor Up-Regulates Molecular Effectors of Tumor Invasion Cancer Res., June 1, 2002; 62(12): 3335 - 3339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. N. Coleman, J. B. Mitchell, and K. Camphausen Tumor Hypoxia: Chicken, Egg, or a Piece of the Farm? J. Clin. Oncol., February 1, 2002; 20(3): 610 - 615. [Full Text] [PDF]
|
|
|
|
 |
|
 News Ann. Onc., January 19, 2002; 13(1): 1 - 5. [Full Text] [PDF]
|
|