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* Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy;
Pathology Department, Regina Elena Cancer Institute, Rome; Italy;
Comparative Toxicology Laboratory, Istituto Superiore di Sanità, Rome; Italy; and
§ Advanced Biotechnology Center, National Institute for Research on Cancer, Genova, Italy
1Correspondence: Experimental Chemotherapy Lab., Regina Elena Cancer Institute, Via delle Messi d’Oro N.156, 00158 Rome, Italy. E-mail: delbufalo{at}ifo.it
We have previously demonstrated that bcl-2 overexpression enhances the metastatic potential of the MCF7 ADR human breast cancer cell line resistant to adriamycin by inducing metastasis-associated properties. To further elucidate the relationship between bcl-2 expression and the metastatic potential of the MCF7 ADR line, we evaluated whether bcl-2 could be also involved in the modulation of the angiogenic phenotype. Four bcl-2-overexpressing clones, a control transfectant clone, and the MCF7 ADR parental line were used for in vitro and in vivo experiments. Bcl-2 overexpression enhanced the synthesis of the hypoxia-stimulated VEGF protein and mRNA. Northern blot analysis demonstrated an increased VEGF mRNA expression in bcl-2-overexpressing clones, and reverse transcription-polymerase chain reaction showed higher levels of the VEGF121 and VEGF165 mRNA isoforms, which are the most active in eliciting angiogenesis. When incorporated into matrigel, supernatants of bcl-2-transfected cells cultured under hypoxic conditions induced an increased angiogenic response in C57BL/6 mice compared with that of control clone. Tumors from bcl-2 transfectants demonstrated increased VEGF expression and neovascularization as compared to the parental line, whereas the apoptosis in in vivo xenografts was similar in control and bcl-2 transfectants. The effect of bcl-2 on angiogenesis was not mediated by p53 protein. These results demonstrate that bcl-2 and hypoxia can act synergistically to modulate VEGF expression and the in vivo angiogenic response in the MCF7 ADR line.—Biroccio, A., Candiloro, A., Mottolese, M., Sapora, O., Albini, A., Zupi, G., Del Bufalo, D. Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line.
Key Words: in vivo matrigel assay • MCF7 ADR • metastasis
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