Hypoxia-inducible factor-1α and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients

doi:10.1186/bcr2452

Breast Cancer Research

Volume 11
Issue 6

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Kallergi G
Markomanolaki H
Giannoukaraki V
Papadaki MA
Strati A
Lianidou ES
Georgoulias V
Mavroudis D
Agelaki S

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Kallergi G
Markomanolaki H
Giannoukaraki V
Papadaki MA
Strati A
Lianidou ES
Georgoulias V
Mavroudis D
Agelaki S
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Research article

Hypoxia-inducible factor-1α and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients

Galatea Kallergi¹ , Harris Markomanolaki¹ , Vicky Giannoukaraki¹ , Maria A Papadaki¹ , Areti Strati² , Evi S Lianidou² , Vassilis Georgoulias¹^,3 , Dimitris Mavroudis¹^,3 and Sofia Agelaki¹^,3

¹Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Voutes, Heraklion, 71110, Greece

²Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, 15771, Greece

³Department of Medical Oncology, University General Hospital of Heraklion, Voutes, Heraklion, 71110, Greece

author email corresponding author email

Breast Cancer Research 2009, 11:R84doi:10.1186/bcr2452


Published:	17 November 2009

Abstract

Introduction

The detection of peripheral blood circulating tumor cells (CTCs) and bone marrow disseminated tumor cells (DTCs) in breast cancer patients is associated with a high incidence of disease relapse and disease-related death. Since hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) play an important role in angiogenesis and tumor progression, the purpose of the current study was to investigate their expression in CTCs.

Methods

The expression of cytokeratins (CK), VEGF, vascular endothelial growth factor receptor-2 (VEGF2), HIF-1α and phosphorylated-focal adhesion kinase (pFAK) in CTCs from 34 patients with metastatic breast cancer who had detectable CK-19 mRNA-positive CTCs was assessed using double staining experiments and confocal laser scanning microscopy. Peripheral blood mononuclear cells (PBMCs) were stained with a monoclonal A45-B/B3 pancytokeratin antibody in combination with either VEGF or VEGFR2 or HIF-1α or pFAK antibodies, respectively.

Results

pFAK expression in circulating tumor cells was detected in 92% of patients whereas expression of VEGF, VEGF2 and HIF-1α was observed in 62%, 47% and 76% of patients, respectively. VEGF, VEGF2, HIF-1α and pFAK were expressed in 73%, 71%, 56% and 81%, respectively, of all the detected CTCs. Vascular endothelial growth mRNA was also detected by quantitative real-time RT-PCR in immunomagnetically-separated CTCs. Double and triple staining experiments in cytospins of immunomagnetically-isolated CTCs showed that VEGF co-expressed with HIF-1α and VEGF2.

Conclusions

The expression of pFAK, HIF-1α, VEGF and VEGF2 in CTCs of patients with metastatic breast cancer could explain the metastatic potential of these cells and may provide a therapeutic target for their elimination.