The natural FGF-trap long pentraxin 3 inhibits lymphangiogenesis and lymphatic dissemination

Abstract

The lymphatic vascular system represents a major route for dissemination of several solid tumors, including melanoma. Even though the members of the Vascular Endothelial Growth Factor family VEGF-C and VEGF-A have been shown to drive tumor lymphangiogenesis, experimental evidence indicates that also the pro-angiogenic factor Fibroblast Growth Factor-2 (FGF2) may play a role in the lymphangiogenic switch by triggering the activation of lymphatic endothelial cells (LECs) in cooperation with VEGFs.The soluble pattern recognition receptor Long Pentraxin 3 (PTX3) acts as a natural FGF trap, thus exerting an oncosuppressive role in FGF-dependent tumors. Here, the capacity of PTX3 to modulate lymphangiogenesis was assessed in vitro and in vivo. The results demonstrate that recombinant human PTX3 inhibits the lymphangiogenic activity exerted by the VEGF-A/FGF2/sphingosine-1-phosphate (VFS) cocktail on human and murine LECs. In keeping with in vitro data, a reduced lymphangiogenic response was observed in a lymphangiogenic Matrigel plug assay following the subcutaneous injection of the VFS cocktail in PTX3-overexpressing transgenic TgN(Tie2-hPTX3) mice when compared to wild-type or Ptx3 null animals. Accordingly, the capacity of B16F10-VEGFC-luc melanoma cells to colonize the primary tumor-draining lymph node after grafting into the foot pad was dramatically impaired in PTX3-overexpressing mice.Together with the observation that both the VFS cocktail and melanoma cell conditioned media caused a significant downregulation of PTX3 expression in LECs, these data indicate that the FGF trap activity of PTX3 may exert a key effect in the modulation of lymphangiogenesis and tumor metastatic dissemination.

Molecular Profiling of Lymphatic Endothelial Cell Activation In Vitro

“…Lymphangiogenic activation is a key step in the formation of new LVs under prolymphangiogenic stimuli. In vitro, a potent activator of LECs is represented by the prolymphangiogenic mixture VEGF-A (40 ng/mL), FGF-2 (40 ng/mL), and S1P (2 µM), also named VFS [17,18]. Here, we verified that treatment of HDLECs with VFS promotes cell activities involved in lymphatic activation, thus allowing us to mimic/recapitulate this process in vitro.…”

“…Despite the widely recognized pivotal role of the lymphatic system in melanoma progression, little is known about the molecular changes that occur in cancer-associated LVs, resulting in the acquisition of tumor-promoting features. In this work, we exploited RNA sequencing to compare the transcriptional profile of primary human lymphatic endothelial cells (HDLECs) treated with a prototypic mix (VFS) of lymphangiogenic stimuli (i.e., VEGF-A, FGF2, and S1P) [17,18], or co-cultured with melanoma cells. This analysis highlights several pathways, mainly involved in vessel development, immune response, and cytokine signaling, that are commonly regulated in both tumor-and VFS-activated HDLECs, thus evidencing general common molecular features in these in vitro modes of lymphatic activation.…”

Cocrystallization of lenvatinib and temozolomide to improve the performance in terms of stability, dissolution, and tabletability

“…The TG-DSC curves of TMZ and LEN show that they are solvent-free forms and decompose with an exothermic peak at 205.2 °C and endothermic peak at 229. 4 A crystal of TMZ-LEN•MeOH was investigated by hot-stage microscopy from room temperature to 170 °C with a heating rate of 10 °C min −1 (Fig. 4).…”

“…Genetic aberrations associated with angiogenic signalling pathways mediated by growth factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), have been correlated with progression in metastatic melanoma. 4,5 Lenvatinib (LEN, Scheme 1) is an orally active multi-kinase inhibitor of VEGFR 1–3, FGF-receptor (FGFR) 1–4, PDGF-receptor (PDGFR)-α, RET, and KIT proto-oncogenes, 6 and it shows antitumor activity in melanoma. 7…”

“…Genetic aberrations associated with angiogenic signalling pathways mediated by growth factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), have been correlated with progression in metastatic melanoma. 4,5 Lenvatinib (LEN, Scheme 1) is an orally active multi-kinase inhibitor of VEGFR 1-3, FGFreceptor (FGFR) 1-4, PDGF-receptor (PDGFR)-α, RET, and KIT proto-oncogenes, 6 and it shows antitumor activity in melanoma. 7 Temozolomide (TMZ) is an oral chemotherapeutic agent that shows response and efficacy in melanoma, and it is also able to cross the blood-brain barrier, giving it a possible role in the treatment of melanoma patients with brain metastases.…”