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

Abstract

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.

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

“…Histological analysis and immunohistochemistry were performed as reported (Marcellini et al, 2006;Pisano et al, 2008).…”

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…Accumulating evidence suggests additional mechanisms. For instance, PlGF up-regulates the expression of angiogenic factors such as VEGF, basic fibroblast growth factor (FGF2), platelet derived growth factor b (PDGFB), and matrix metalloproteinases (MMPs), among other molecules (Roy et al 2005;Marcellini et al 2006). Furthermore, activation of FLT1 by PlGF induces an intermolecular FLT1:VEGFR-2 cross talk that amplifies VEGF/VEGFR-2 signaling, suggesting that endothelial cells are capable of enhancing their own responsiveness to VEGF by releasing PlGF (Autiero et al 2003).…”

“…In any case, it is worth noting that a larger number of studies report a proangiogenic effect for PlGF when it is expressed endogenously by tumor or stroma cells, or when a PlGF transgene is modestly overexpressed by tumor cells (Hiratsuka et al 2001;Adini et al 2002;Li et al 2006;Marcellini et al 2006;Kerber et al 2008;Tarallo et al 2010). Furthermore, genetic neutralization of PlGF inhibits-not stimulates-vessel growth in adipose tissue, tumors, and other injured, ischemic, or inflamed tissues (Table 1).…”

PGF isoforms, PLGF-1 and PGF-2 and the PGF receptor, neuropilin, in human breast cancer: Prognostic significance

“…Different VEGF family member appears to have a specific function: VEGF-C and VEGF-D both are primarily lymphangiogenic factors, while VEGF and VEGF-B are primarily angiogenic (2). In addition, VEGF directly promotes proliferation and/or migration of VEGF receptor-expressing tumour cells and they are also involved in mobilization of endothelial and haematopoietic stem cells (HSCs) from the bone marrow and their recruitment at the tumour site where they contribute to tumour angiogenesis (3).…”