Long Pentraxin-3 Inhibits Epithelial–Mesenchymal Transition in Melanoma Cells

Abstract

During melanoma progression, malignant melanocytes are reprogrammed into mesenchymal-like cells through to an epithelial-mesenchymal transition (EMT) process associated with the acquisition of an invasive, prometastatic phenotype. The fibroblast growth factor-2 (FGF2)/FGF receptor (FGFR) system plays a pivotal role in melanoma, leading to autocrine/paracrine induction of tumor cell proliferation and angiogenesis. Long pentraxin-3 (PTX3) interacts with FGF2, and other FGF family members, inhibiting FGF-dependent neovascularization and tumor growth. Here, PTX3 protein and the PTX3-derived acetylated pentapeptide Ac-ARPCA-NH 2 inhibit FGF2-driven proliferation and downstream FGFR signaling in murine melanoma B16-F10 cells. Moreover, human PTX3-overexpressing hPTX_B16-F10 cells are characterized by the reversed transition from a mesenchymal to an epithelial-like appearance, inhibition of cell proliferation, loss of clonogenic potential, reduced motility and invasive capacity, downregulation of various mesenchymal markers, and upregulation of the epithelial marker E-cadherin. Accordingly, PTX3 affects cell proliferation and EMT transition in human A375 and A2058 melanoma cells. Also, hPTX_B16-F10 cells showed a reduced tumorigenic and metastatic activity in syngeneic C57BL/6 mice. In conclusion, PTX3 inhibits FGF/FGFR-driven EMT in melanoma cells, hampering their tumorigenic and metastatic potential. These data represent the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma and indicate that PTX3 or its derivatives may represent the basis for the design of novel therapeutic approaches in FGF/FGFRdependent tumors, including melanoma. Mol Cancer Ther; 12(12); 2760-71. Ó2013 AACR.

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…Indeed, FGF2 appears to act on fibroblasts and endothelial cells in order to modulate the tumor microenvironment, thus favoring melanoma growth, neovascularization, invasion, and metastasis [91].…”

“…Natural FGF binders (Table 2) have been identified in the ECM and body fluids. Among them, thrombospondin-1 (TSP-1), long pentraxin-3 (PTX3), heparin [87,91,116] and soluble decoy FGFRs [117] have been exploited for therapeutic purposes. For instance, molecular modeling and protein-protein interaction studies were used to map the amino acid residues involved in TSP-1/FGF2 and PTX3/FGF2 binding.…”

La signalisation FGF/FGFR : implication dans l’oncogenèse et perspectives thérapeutiques

“…Ce changement est marqué par la régulation positive de l'expression d'E-cadhérine, une molécule d'adhérence et marqueur du phénotype épithélial, après exposition des cellules tumorales à la pentraxine. Il s'agit de la première et seule preuve de l'implication de bFGF dans la transition épithélio-mésenchymateuse, nécessaire à l'invasion tumorale et à la dissémination métastatique [26].…”

The Long Pentraxin PTX3 as a Key Component of Humoral Innate Immunity and a Candidate Diagnostic for Inflammatory Diseases

“…Therefore, PTX3 overexpression in TRAMP-C2 cells impedes their angiogenic and tumorigenic potential when grafted into syngeneic or immunodeficient athymic male mice [85]. PTX3 has also the capacity to inhibit the FGF2-driven proliferation and downstream FGF receptor signaling in murine melanoma cells [86]. PTX3 overexpression in these cells inhibits their transition from an epithelial-like to a mesenchymal appearance and their proliferation, and reduces their motility and invasive capacity [86].…”

“…PTX3 overexpression in these cells inhibits their transition from an epithelial-like to a mesenchymal appearance and their proliferation, and reduces their motility and invasive capacity [86]. Accordingly, the in vivo tumorigenic and metastatic activity of B16-F10 murine melanoma cells is reduced by PTX 3 overexpression [86]. …”