Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features

Am J Pathol. 1999 Dec;155(6):1967-76. doi: 10.1016/S0002-9440(10)65515-0.


Experimental evidence has shown, both in vitro and in animal models, that neoplastic growth and subsequent metastasis formation depend on the tumor's ability to induce an angiogenic switch. This requires a change in the balance of angiogenic stimulators and inhibitors. To assess the potential role of angiogenesis factors in human thyroid tumor growth and spread, we analyzed their expression by semiquantitative RT-PCR and immunohistochemistry in normal thyroid tissues, benign lesions, and different thyroid carcinomas. Compared to normal tissues, in thyroid neoplasias we observed a consistent increase in vascular endothelial growth factor (VEGF), VEGF-C, and angiopoietin-2 and in their tyrosine kinase receptors KDR, Flt-4, and Tek. In particular, we report the overexpression of angiopoietin-2 and VEGF in thyroid tumor progression from a prevascular to a vascular phase. In fact, we found a strong association between tumor size and high levels of VEGF and angiopoietin-2. Furthermore, our results show an increased expression of VEGF-C in lymph node invasive thyroid tumors and, on the other hand, a decrease of thrombospondin-1, an angioinhibitory factor, in thyroid malignancies capable of hematic spread. These results suggest that, in human thyroid tumors, angiogenesis factors seem involved in neoplastic growth and aggressiveness. Moreover, our findings are in keeping with a recent hypothesis that in the presence of VEGF, angiopoietin-2 may collaborate at the front of invading vascular sprouts, serving as an initial angiogenic signal that accompanies tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / metabolism*
  • Angiogenesis Inhibitors / metabolism*
  • Angiopoietin-1
  • Angiopoietin-2
  • Blotting, Northern
  • Down-Regulation
  • Endothelial Growth Factors / metabolism
  • Humans
  • Immunohistochemistry
  • Lymphatic Metastasis
  • Lymphokines / metabolism
  • Membrane Glycoproteins / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Physiologic
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • RNA / analysis
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thrombospondins / metabolism
  • Thyroid Gland / metabolism
  • Thyroid Gland / pathology
  • Thyroid Neoplasms / metabolism*
  • Thyroid Neoplasms / pathology*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factors


  • ANGPT1 protein, human
  • Angiogenesis Inducing Agents
  • Angiogenesis Inhibitors
  • Angiopoietin-1
  • Angiopoietin-2
  • Endothelial Growth Factors
  • Lymphokines
  • Membrane Glycoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Growth Factor
  • Thrombospondins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • RNA
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1