ORIGINAL ARTICLE

Expression of vascular endothelial growth factor, hypoxia inducible factor 1, and carbonic anhydrase IX in human tumours

A M Jubb¹, T Q Pham¹, A M Hanby², G D Frantz¹, F V Peale¹, T D Wu³, H W Koeppen¹ and K J Hillan¹

¹ Department of Pathology, Genentech Inc, South San Francisco, CA94080, USA
² Department of Academic Unit of Pathology, University of Leeds, Leeds, UK
³ Department of Bioinformatics, Genentech Inc

Correspondence to:
Correspondence to:
A Jubb
Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA; adrianj{at}gene.com

Aims: To measure vascular endothelial growth factor (VEGF-A) mRNA in a large, diverse cohort of tumours and to investigate whether VEGF-A expression is associated with markers of hypoxia, including hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase IX (CA9).

Methods: The expression of VEGF-A and CA9 was assessed in 5067 fresh frozen human tissue samples and 238 cell lines by DNA microarray analysis. In addition, tissue microarrays were constructed from 388 malignancies to investigate the expression of VEGF-A and HIF-1 by in situ hybridisation and immunohistochemistry, respectively.

Results: VEGF-A was significantly upregulated in primary malignancies of the breast, cervix, colon and rectum, oesophagus, head and neck, kidney, ovary, skin, urinary system, and white blood cells by DNA microarray analysis. However, VEGF-A expression only correlated with CA9 expression in renal tissues. In the tissue microarrays, HIF-1 positive cores showed a significant increase in VEGF-A expression in lung, ovary, soft tissue, and thyroid malignancies.

Conclusions: The expression of VEGF-A is upregulated in a large proportion of human malignancies, and may be associated with markers of hypoxia. VEGF-A expression can be induced in the absence of hypoxia and hypoxia does not always provoke VEGF-A upregulation in tumours.

Keywords: vascular endothelial growth factor; hypoxia inducible factor one alpha; carbonic anhydrase IX; angiogenesis; neoplasia

Abbreviations: CA9, carbonic anhydrase IX; CHO, Chinese hamster ovary; H&E, haematoxylin and eosin; HIF-1, hypoxia inducible factor 1; IHC, immunohistochemistry; ISH, in situ hybridisation; PCR, polymerase chain reaction; TMA, tissue microarray; VEGF-A, vascular endothelial growth factor A; VHL, von Hippel-Lindau

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