Hypoxia-inducible factors 1alpha and 2alpha are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin

Melanoma Res. 2003 Oct;13(5):493-501. doi: 10.1097/00008390-200310000-00008.


Hypoxia is a key regulatory factor in tumour growth, activating angiogenesis, glycolysis and cell migration. It is readily recognized by the intracellular accumulation of hypoxia-inducible factor 1alpha (HIF1alpha) and HIF2alpha. Accumulation of HIF1alpha and HIF2alpha was detected immunohistochemically in a series of 46 nodular malignant melanomas of the skin (epithelioid cell variant), treated with wide local excision. The results were correlated with vascular density (VD) and expression of the angiogenesis-stimulating factors vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). Further associations were sought with patient prognosis and the important histopathological features of Breslow's thickness, Clark's level of invasion, mitotic rate, inflammatory cell infiltrates and tumour ulceration. HIF1alpha and HIF2alpha accumulation in malignant melanomas was directly correlated with VEGF expression. Tumours with high VEGF or HIF2alpha expression were associated with a poorer prognosis on both univariate and multivariate analyses. Tumours displaying high VD were also associated with a poor prognosis, but only on univariate analysis. Such vascularized malignant melanomas had only a limited inflammatory cell response. TP and VEGF were frequently co-expressed. The value of Breslow's thickness and Clark's level in prognosis was reaffirmed, although only on univariate analysis. Overexpression of the transcription factors HIF1alpha and HIF2alpha are linked to VEGF expression in nodular malignant melanomas. Loss of immune surveillance, as indicated by a limited inflammatory cell response, was also associated with high angiogenic activity. HIF2alpha, VEGF and, to a lesser extent, VD are important prognostic factors in these cutaneous tumours.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Female
  • Head and Neck Neoplasms / metabolism
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • Male
  • Melanoma / diagnosis*
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Middle Aged
  • Neoplasm Metastasis
  • Neovascularization, Pathologic
  • Platelet Endothelial Cell Adhesion Molecule-1 / biosynthesis
  • Prognosis
  • Skin Neoplasms / diagnosis*
  • Skin Neoplasms / metabolism*
  • Thymidine Phosphorylase / metabolism
  • Time Factors
  • Trans-Activators / biosynthesis*
  • Transcription Factors / biosynthesis*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor A / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Trans-Activators
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • endothelial PAS domain-containing protein 1
  • Thymidine Phosphorylase