Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Experimental Therapeutics
  • Published:

Hypoxia-associated spontaneous pulmonary metastasis in human melanoma xenografts: involvement of microvascular hot spots induced in hypoxic foci by interleukin 8

British Journal of Cancer volume 86, pages 301–308 (2002)Cite this article

Abstract

The aim of this study was to investigate whether tumour hypoxia and/or vascular hot spots promote the development of metastatic disease. The D-12 human melanoma xenograft line was used as a tumour model. Hypoxia and vascular hot spots were detected by immunohistochemistry using pimonidazole as a hypoxia marker and anti-CD31 antibody to visualize endothelial cells. Vascular hot spots were found to be induced in hypoxic foci, owing to hypoxia-induced up-regulation of angiogenesis stimulatory factors. This effect was mediated by interleukin 8 and possibly also by vascular endothelial growth factor. Interleukin 8 positive foci showed a high degree of co-localization with hypoxic foci, as revealed by immunohistochemistry. The incidence of spontaneous pulmonary metastases was associated with the density of hypoxic foci, the density of interleukin 8 positive foci and the density of vascular hot spots in the primary tumour. Treatment with neutralizing antibody against interleukin 8 and/or vascular endothelial growth factor resulted in hypoxia-induced necrosis rather than hypoxia-induced vascular hot spots and inhibited metastasis. Our study suggests a cause-effect relationship between hypoxia and metastasis in cancer and hence an elevated probability of metastatic disease in patients having primary tumours characterized by high densities of hypoxic foci and vascular hot spots.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Bar-Eli M (1999) Role of interleukin-8 in tumor growth and metastasis of human melanoma. Pathobiology 67: 12–18

    Article  CAS  Google Scholar 

  • Brizel DM, Scully PS, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, Dewhirst MW (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56: 941–943

    CAS  PubMed  Google Scholar 

  • Danielsen T, Rofstad EK (2000) The constitutive level of vascular endothelial growth factor (VEGF) is more important than hypoxia-induced VEGF up-regulation in the angiogenesis of human melanoma xenografts. Br J Cancer 82: 1528–1534

    Article  CAS  Google Scholar 

  • Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18: 4–25

    Article  CAS  Google Scholar 

  • Fidler IJ, Ellis LM (1994) The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79: 185–188

    Article  CAS  Google Scholar 

  • Griffiths L, Dachs GU, Bicknell R, Harris AL, Stratford IJ (1997) The influence of oxygen tension and pH on the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast tumor cells grown in vitro and in vivo. Cancer Res 57: 570–572

    CAS  PubMed  Google Scholar 

  • Hartmann A, Kunz M, Köstlin S, Gillitzer R, Toksoy A, Bröcker E-B, Klein CE (1999) Hypoxia-induced up-regulation of angiogenin in human malignant melanoma. Cancer Res 59: 1578–1583

    CAS  PubMed  Google Scholar 

  • Horsman MR (1995) Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours: a review. Acta Oncol 34: 571–587

    Article  CAS  Google Scholar 

  • Höckel M, Schlenger K, Arai B, Mitze M, Schäffer U, Vaupel P (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56: 4509–4515

    PubMed  Google Scholar 

  • Li C-J, Shan S, Huang Q, Braun RD, Lanzen J, Hu K, Lin P, Dewhirst MW (2000) Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92: 143–147

    Article  CAS  Google Scholar 

  • Nowell PC (1986) Mechanisms of tumor progression. Cancer Res 46: 2203–2207

    CAS  PubMed  Google Scholar 

  • Rofstad EK (1994) Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern. Br J Cancer 70: 804–812

    Article  CAS  Google Scholar 

  • Rofstad EK (2000) Microenvironment-induced cancer metastasis. Int J Radiat Biol 76: 589–605

    Article  CAS  Google Scholar 

  • Rofstad EK, Danielsen T (1999) Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer 80: 1697–1707

    Article  CAS  Google Scholar 

  • Rofstad EK, Graff BA (2001) Thrombospondin-1-mediated metastasis suppression by the primary tumor in human melanoma xenografts. J Invest Dermatol 117: 1042–1049

    Article  CAS  Google Scholar 

  • Rofstad EK, Halsør EF (2000) Vascular endothelial growth factor, interleukin-8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res 60: 4932–4938

    CAS  PubMed  Google Scholar 

  • Rofstad EK, Måseide K (1999) Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumours. Int J Radiat Biol 75: 1377–1393

    Article  CAS  Google Scholar 

  • Rofstad EK, Sundfør K, Lyng H, Tropé CG (2000) Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis. Br J Cancer 83: 354–359

    Article  CAS  Google Scholar 

  • Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K (1999) Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 5: 3711–3721

    CAS  PubMed  Google Scholar 

  • Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49: 6449–6465

    CAS  PubMed  Google Scholar 

  • Weidner N (1995) Intratumor microvessel density as a prognostic factor in cancer. Am J Pathol 147: 9–19

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu L, Xie K, Mukaida N, Matsushima K, Fidler IJ (1999) Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells. Cancer Res 59: 5822–5829

    CAS  PubMed  Google Scholar 

  • Young SD, Marshall RS, Hill RP (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci USA 85: 9533–9537

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Berit Mathiesen, Heidi Rasmussen, Kristin Nilsen and Kanthi Galappathi for excellent technical assistance. Financial support was received from The Norwegian Cancer Society.

Author information

Authors and Affiliations

  1. Department of Biophysics, Group of Radiation Biology and Tumor Physiology, Institute for Cancer Research, The Norwegian Radium Hospital, N-0310, Oslo, Norway

    E K Rofstad & E F Halsør

Authors
  1. E K Rofstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E F Halsør
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E K Rofstad.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rofstad, E., Halsør, E. Hypoxia-associated spontaneous pulmonary metastasis in human melanoma xenografts: involvement of microvascular hot spots induced in hypoxic foci by interleukin 8. Br J Cancer 86, 301–308 (2002). https://doi.org/10.1038/sj.bjc.6600052

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bjc.6600052

Keywords

This article is cited by

Search

Advanced search

Quick links