Neovascularization in human germ cell tumors correlates with a marked increase in the expression of the vascular endothelial growth factor but not the placenta-derived growth factor

Giuseppe Viglietto, Annunciata Romano, Domenico Maglione, Marco Rambaldi, Iole Paoletti, Carmine T. Lago, Daniela Califano, Carmen Monaco, Alba Mineo, Giovanni Santelli, Giovanni Manzo, Gerardo Botti, Gennaro Chiappetta, M. Graziella Persico

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Abstract

Neoangiogenesis is a prerequisite for tumor growth and metastasis. In germ cell cancer patients with the disease limited to the testicle (stage A), tumor-associated neovascularization is predictive of metastatic disease (stage B). To investigate the molecular mechanisms underlying neovascularization in human germ cell tumors (GCTs), we analysed the expression of two angiogenic growth factors, vascular endothelial growth factor (VEGF) and placenta growth factor (P1GF), and of their receptors (FLT-1) and Flk-1/KDR) in a panel of testicular tumors. In this study we show a marked increase in VEGF expression in 36/44 (81.8%) primary testicular-derived GCTs, as compared to normal testis, that significantly correlates with a high density of intratumor microvessels (r = 0.72461, P <0.001; n = 24). As determined by RT-PCR and/or Western blot, the predominant VEGF isoforms expressed in GCTs are the VEGF121 and VEGF165 which are more efficiently secreted by the cells, and thus more active in eliciting angiogenesis. Conversely, in the case of P1GF, only a weak correlation with the vascular density of tumors is observed (r = 0.26599, P <0.05; n = 24). Northern blot analysis also revealed significant up-regulation of VEGF/P1GF receptors in highly vascularized germ cell tumors, compared to normal testes. These findings suggest that VEGF may act in a paracrine manner to induce neovascularization, oedema extravasation and cyst formation in human germ cell tumors. The correlation between VEGF expression and the vascular density of tumors, suggest that the evaluation of VEGF expression may be of help in predicting patients at risk for metastatic diseases. Finally, we demonstrate that VEGF up-regulation may occur at the RNA level since no gene amplification is observed; conversely, in in vitro models such as the embryonal stem cell line NTERA-2 and the choriocarcinoma JEG-3 cell line, VEGF (but not P1GF) mRNA expression is regulated by hypoxic stress.

Original languageEnglish
Pages (from-to)577-587
Number of pages11
JournalOncogene
Volume13
Issue number3
Publication statusPublished - 1996

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Keywords

  • Angiogenesis
  • Germ cell tumors
  • P1GF
  • Vascular count
  • VEGF

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Viglietto, G., Romano, A., Maglione, D., Rambaldi, M., Paoletti, I., Lago, C. T., Califano, D., Monaco, C., Mineo, A., Santelli, G., Manzo, G., Botti, G., Chiappetta, G., & Persico, M. G. (1996). Neovascularization in human germ cell tumors correlates with a marked increase in the expression of the vascular endothelial growth factor but not the placenta-derived growth factor. Oncogene, 13(3), 577-587.