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Open Access Research article

Fast growth associated with aberrant vasculature and hypoxia in fibroblast growth factor 8b (FGF8b) over-expressing PC-3 prostate tumour xenografts

Johanna Tuomela12*, Tove J Grönroos3, Maija P Valta1, Jouko Sandholm4, Aleksi Schrey5, Jani Seppänen12, Päivi Marjamäki3, Sarita Forsback6, Ilpo Kinnunen5, Olof Solin7, Heikki Minn8 and Pirkko L Härkönen19

Author Affiliations

1 Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland

2 Pharmatest Services Ltd., Turku, Finland

3 Turku PET Centre, MediCity Preclinical Research Laboratory, University of Turku and Åbo Akademi University, Turku, Finland

4 Cell Imaging Core, Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland

5 Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital, University of Turku, Turku, Finland

6 Turku PET Centre, Radiopharmaceutical Chemistry Laboratory, University of Turku and Åbo Akademi University, Turku, Finland

7 Turku PET Centre, Accelerator Laboratory, MediCity Preclinical Research Laboratory, University of Turku and Åbo Akademi University, Turku, Finland

8 Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland

9 Department of Laboratory Medicine, MAS University Hospital, Lund University, Malmö, Sweden

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BMC Cancer 2010, 10:596  doi:10.1186/1471-2407-10-596

Published: 30 October 2010

Abstract

Background

Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model.

Methods

Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([18F]FDG) and hypoxia ([18F]EF5), and intratumoral polarographic measurements of pO2.

Results

Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO2 measurements, [18F]EF5 and [18F]FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls.

Conclusion

FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts.