© 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.
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