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Research Article

Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers

  • Jen-Tsan Chi equal contributor,

    equal contributor Contributed equally to this work with: Jen-Tsan Chi, Zhen Wang

    Affiliations: Department of Biochemistry, Stanford University School of Medicine, Palo Alto, California, United States of America, The Institute of Genome Sciences and Policy, Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, United States of America

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  • Zhen Wang equal contributor,

    equal contributor Contributed equally to this work with: Jen-Tsan Chi, Zhen Wang

    Affiliation: Department of Surgery, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • Dimitry S. A Nuyten,

    Affiliation: Diagnostic Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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  • Edwin H Rodriguez,

    Affiliation: Department of Biochemistry, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • Marci E Schaner,

    Affiliation: Department of Biochemistry, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • Ali Salim,

    Affiliations: Department of Surgery, Stanford University School of Medicine, Palo Alto, California, United States of America, Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • Yun Wang,

    Affiliations: Department of Gynecologic Oncology, The Norwegian Radium Hospital, Oslo, Norway, Department of Genetics, The Norwegian Radium Hospital, Oslo, Norway

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  • Gunnar B Kristensen,

    Affiliation: Department of Gynecologic Oncology, The Norwegian Radium Hospital, Oslo, Norway

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  • Åslaug Helland,

    Affiliations: Department of Gynecologic Oncology, The Norwegian Radium Hospital, Oslo, Norway, Department of Genetics, The Norwegian Radium Hospital, Oslo, Norway

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  • Anne-Lise Børresen-Dale,

    Affiliation: Department of Genetics, The Norwegian Radium Hospital, Oslo, Norway

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  • Amato Giaccia,

    Affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • Michael T Longaker,

    Affiliation: Department of Surgery, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • Trevor Hastie,

    Affiliation: Health Research and Policy, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • George P Yang,

    Affiliations: Department of Surgery, Stanford University School of Medicine, Palo Alto, California, United States of America, Palo Alto VA Health Care System, Palo Alto, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • Marc J van de Vijver,

    Affiliation: Diagnostic Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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  • Patrick O Brown mail

    To whom correspondence should be addressed. E-mail: pbrown@pmgm2.stanford.edu

    Affiliations: Department of Biochemistry, Stanford University School of Medicine, Palo Alto, California, United States of America, Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California, United States of America

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  • Published: January 24, 2006
  • DOI: 10.1371/journal.pmed.0030047

Reader Comments (2)

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RE: eLetter from Dr. Mittal

Posted by plosmedicine on 30 Mar 2009 at 23:57 GMT

Author: Jen-Tsan Chi
Position: Assistant Professor
Institution: Duke
E-mail: chi00002@mc.duke.edu
Additional Authors: Trevor Hastie, Patrick Brown
Submitted Date: July 19, 2006
Published Date: July 20, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

Dr. Mittal has raised the possibility that the different degrees of hypoxia responses we observed among different cell lines and different types of renal cell carcinoma (RCC) could be explained simply the level of their mitotic activities.

As to the issue of different cultured cells, we wish to clarify that all the cultured cells used in this study are primary non-transformed cells. Therefore, there is no distinction between carcinoma vs. stromal cells as referred in the letter. Although these cells were cultured in different medium conditions, but there were not appreciable differences in their doubling time between the epithelial cells (HMEC and RPTEC) vs. stromal cells (fibroblast and endothelial cells).

As to the relationship between mitotic activities and hypoxia response in the tumors, it is frequently assumed that highly proliferative tumors lead to increased oxygen consumption, lower intratumor oxygen and tumor hypoxia response. Although we cannot rule out the role of mitotic activities in the strong hypoxia response observed in the clear cell RCC, we postulated that main driver for the strong hypoxia response in clear cell RCC is loss of functional VHL due to the high frequency of VHL mutation in these tumors and the well-documented role of VHL in the degradation of HIF-1a protein. This view is further supported by the similar high hypoxia response in the clear cell RCC cell lines [1]. We have also tested the relationship between the proliferation activities and hypoxia response in breast cancers. We used a gene signature obtained by the synchronized cultured of Hela cells in a previous study as a molecular gauge of proliferative activities[2]. When we compared the level of this 'proliferative' and 'hypoxia response' in the 295 tumors of NKI dataset, we noted a lack of correlation between these two activities (cor=0.186). On the other hand, there is a good correlation between the 'proliferative'and 'wound'response defined previously by the fibroblast serum response (cor=0.72) [3].

Taken together, we think proliferative activities are not the main determinant of hypoxia response in our analysis. There is still a need to perform additional studies to understand the molecular nature of the diversity of hypoxia response among different cell types and various human tumors. One potential approach is to integrate the gene expression data with other related information to determine the physiological parameters and genetic alterations linked to the strong hypoxia responses[4].

References

1. Kaelin WG, Jr. (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2: 673-682.
2. Whitfield ML, Sherlock G, Saldanha AJ, Murray JI, Ball CA, et al. (2002) Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell 13: 1977-2000.
3. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, et al. (2004) Gene Expression Signature of Fibroblast Serum Response Predicts Human Cancer Progression: Similarities between Tumors and Wounds. PLoS Biol 2: E7.
4. Adler AS, Lin M, Horlings H, Nuyten DS, van de Vijver MJ, et al. (2006) Genetic regulators of large-scale transcriptional signatures in cancer. Nat Genet 38: 421-430.

No competing interests declared.