This Article Full Text Full Text (PDF) All Versions of this Article: 1078-0432.CCR-06-1967v1 13/7/1971    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rofstad, E. K. Articles by Ruud, E.-B. M. Search for Related Content PubMed PubMed Citation Articles by Rofstad, E. K. Articles by Ruud, E.-B. M. Related Collections Related Article

Fluctuating and Diffusion-Limited Hypoxia in Hypoxia-Induced Metastasis

Authors' Affiliation: Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway

Requests for reprints: Einar K. Rofstad, Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. Phone: 47-2278-1206; Fax: 47-2278-1207; E-mail: einar.k.rofstad{at}rr-research.no.

Purpose: Most tumors develop regions with hypoxic cells during growth, owing to permanent limitations in oxygen diffusion (chronic or diffusion-limited hypoxia) and/or transient limitations in blood perfusion (acute or fluctuating hypoxia). The aim of this study was to investigate the relative significance of chronic and acute hypoxia in the development of metastatic disease.

Experimental Design: D-12 and R-18 human melanoma xenografts were used as models of human cancer. D-12 tumors metastasize to the lungs, whereas R-18 tumors develop lymph node metastases. Fraction of radiobiologically hypoxic cells (HF_Rad) was measured in individual primary tumors by using a radiobiological assay based on the paired survival curve method. Fraction of immunohistochemically hypoxic cells (HF_Imm) was assessed in the same tumors by using a pimonidazole-based immunohistochemical assay optimized with respect to achieving selective staining of chronically hypoxic cells. HF_Imm and the difference between HF_Rad and HF_Imm, HF_Rad – HF_Imm, were verified to be adequate variables for fraction of chronically hypoxic cells and fraction of acutely hypoxic cells, respectively.

Results: Chronic as well as acute hypoxia were found to promote spontaneous metastasis of D-12 and R-18 tumors. Acute hypoxia influenced metastasis to a greater extent than chronic hypoxia, partly because the fraction of acutely hypoxic cells was larger than the fraction of chronically hypoxic cells in most tumors and partly because acutely hypoxic cells showed a higher metastatic potential than chronically hypoxic cells.

Conclusions: It may be beneficial to focus on fluctuating hypoxia rather than diffusion-limited hypoxia when searching for hypoxia-related prognostic variables and predictive assays.

Related Article

Hypoxia and Metastasis

Naz Chaudary and Richard P. Hill
Clin. Cancer Res. 2007 13: 1947-1949. [Full Text] [PDF]

This article has been cited by other articles:

				A. Mayer, M. Hockel, A. Wree, C. Leo, L.-C. Horn, and P. Vaupel Lack of Hypoxic Response in Uterine Leiomyomas despite Severe Tissue Hypoxia Cancer Res., June 15, 2008; 68(12): 4719 - 4726. [Abstract] [Full Text] [PDF]

				P. Vaupel Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis Oncologist, May 1, 2008; 13(suppl_3): 21 - 26. [Abstract] [Full Text] [PDF]

				S. Supiot, R. P. Hill, and R. G. Bristow Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53 Mol. Cancer Ther., April 1, 2008; 7(4): 993 - 999. [Abstract] [Full Text] [PDF]

				N. Chan, M. Koritzinsky, H. Zhao, R. Bindra, P. M. Glazer, S. Powell, A. Belmaaza, B. Wouters, and R. G. Bristow Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance Cancer Res., January 15, 2008; 68(2): 605 - 614. [Abstract] [Full Text] [PDF]