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(American Journal of Pathology. 2006;169:643-654.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051041

Increased Melanoma Growth and Metastasis Spreading in Mice Overexpressing Placenta Growth Factor

Marcella Marcellini*, Naomi De Luca{dagger}, Teresa Riccioni*, Alessandro Ciucci{ddagger}, Angela Orecchia{dagger}, Pedro Miguel Lacal§, Federica Ruffini§, Maurizio Pesce, Francesca Cianfarani{dagger}, Giovanna Zambruno{dagger}, Augusto Orlandi{ddagger} and Cristina Maria Failla{dagger}

From the Laboratory of Experimental Angiogenesis,* Sigma Tau, Rome; the Laboratories of Molecular and Cell Biology{dagger} and Molecular Oncology,§ Istituto Dermopatico dell’Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Rome; the Anatomic Pathology Institute,{ddagger} Tor Vergata University, Rome; and the Laboratory of Vascular Biology and Gene Therapy, Centro Cardiologico Monzino–Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy

Placenta growth factor (PlGF), a member of the vascular endothelial growth factor family, plays an important role in adult pathological angiogenesis. To further investigate PlGF functions in tumor growth and metastasis formation, we used transgenic mice overexpressing PlGF in the skin under the control of the keratin 14 promoter. These animals showed a hypervascularized phenotype of the skin and increased levels of circulating PlGF with respect to their wild-type littermates. Transgenic mice and controls were inoculated intradermally with B16-BL6 melanoma cells. The tumor growth rate was fivefold increased in transgenic animals compared to wild-type mice, in the presence of a similar percentage of tumor necrotic tissue. Tumor vessel area was increased in transgenic mice as compared to controls. Augmented mobilization of endothelial and hematopoietic stem cells from the bone marrow was observed in transgenic animals, possibly contributing to tumor vascularization. The number and size of pulmonary metastases were significantly higher in transgenic mice compared to wild-type littermates. Finally, PlGF promoted tumor cell invasion of the extracellular matrix and increased the activity of selected matrix metalloproteinases. These findings indicate that PlGF, in addition to enhancing tumor angiogenesis and favoring tumor growth, may directly influence melanoma dissemination.




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