Increased melanoma growth and metastasis spreading in mice overexpressing placenta growth factor.
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.
Marcellini
Marcella
M
Laboratory of Experimental Angiogenesis, Sigma Tau, Rome, Italy.
De Luca
Naomi
N
Riccioni
Teresa
T
Ciucci
Alessandro
A
Orecchia
Angela
A
Lacal
Pedro Miguel
PM
Ruffini
Federica
F
Pesce
Maurizio
M
Cianfarani
Francesca
F
Zambruno
Giovanna
G
Orlandi
Augusto
A
Failla
Cristina Maria
CM
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008545:Melanoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology*; D009389:Neovascularization, Pathologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D000072483:Placenta Growth Factor; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1