Cell motility and invasion are crucial events for the spread of cancer and, consequently, the metastatic process. Platelet-derived growth factor (PDGF) is not only capable of stimulating the proliferation of SH-SY5Y human neuroblastoma cells, but also their migration and invasion through an extracellular matrix barrier. Experiments using wortmannin and PD98059, specific inhibitors of the phosphatidylinositol 3-kinase (PI3-K) and of the mitogen-activated protein kinases (ERK 1 and 2) signaling, respectively, show that the activation of both pathways is required for the PDGF-induced cell motility responses. We have previously shown that somatostatin inhibits cell division and ERK 1/2 and Ras activity in SH-SY5Y cells. We report here that it is also capable of potently and effectively inhibiting their PDGF-stimulated migration and invasion. The inhibitory effect of somatostatin is sensitive to pertussis toxin. Although somatostatin does not affect PI3-K, it inhibits ERK 1/2 and the small G-protein Rac activation and ruffle formation induced by PDGF. These results indicate that somatostatin can be considered an anti-migratory and antiinvasive agent that acts by inhibiting ERK 1/2 signaling and the PI3-K pathway via the inhibition of Rac in SH-SY5Y cells.

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1 Prostaglandin E 1 (PGE 1 , alprostadil) is used as a vasodilator for the treatment of peripheral vascular diseases. 2 Previous reports suggested a pro-angiogenic e ect for PGE 1 . 3 We studied the in vitro and in vivo e ect of PGE 1 , complexed with a-cyclodextrin, on the angiogenic process. Contrary to what was expected, we found that, in human umbilical vein endothelial cells (HUVECs), PGE 1 inhibited proliferation, migration and capillary-like structure formation in Matrigel. 4 By RT ± PCR studies, the expression of the EP 2 and EP 3 subtypes of the PG receptor was detected in HUVECs. 5 PGE 1 alone stimulated adenylate cyclase activity at micromolar concentrations, while at nanomolar concentrations potentiated the forskolin-induced cAMP accumulation. 6 8-Bromoadenosine-3':5'-cyclic monophosphate (Br-cAMP) mimicked the inhibitory e ect of PGE 1 on endothelial cell growth, motility and tube formation. 7 Sulprostone, an agonist at the EP 3 subtype of PG receptors, mimicked the in vitro antiangiogenic e ects of PGE 1 , while butaprost, an EP 2 receptor agonist, had no e ect. 8 Finally, in the plug assay model of angiogenesis in mice, PGE 1 showed a strong inhibitory e ect on Matrigel neovascularization. 9 Thus, PGE 1 possesses strong anti-angiogenic activity in vitro and in vivo.

The aim of the present research was to study the relationship between chemical structure and antiangiogenic activity of endostatin. Four peptides, containing about 40 amino acid residues, designed to cover nearly the whole sequence of endostatin, were synthesized by the solid-phase method. They were termed Fragment I (sequence 6-49), II (sequence 50-92), III (sequence 93-133), and IV (sequence 134-178), with the latter bearing the original disulfide bond Cys135-Cys165. These peptides were tested for their ability to inhibit endothelial cell proliferation, migration, and both in vitro and in vivo angiogenesis assays in matrigel. Fragments I and IV inhibited cell proliferation and cell migration with a potency and an efficacy higher than that of the full length endostatin. Fragment I was also active in inhibiting in vitro the formation of tubules and in vivo the vascularization of the matrigel. Fragments II and III were devoid of antiangiogenic activity. We propose to use the peptides 6-49 and 134-178 as angiogenesis inhibitors in substitution of full length endostatin, in therapeutic applications for cancer, rheumatoid arthritis, and retinopathies.

As little is known about the role of cadherin-mediated cell-cell adhesion in astrocytes and its alteration in migrating and invasive glioblastomas, we investigated its molecular composition and organisation in primary cultured astrocytes and the T98G and U373MG glioblastoma cell lines. Biochemical and morphological analysis indicated that all three cell types express all of the structural components of the adhesion system, including the LIN-7 PDZ protein,a novel component involved in the organisation of the junctional domain in epithelia and neurons. However, only the astrocytes and T98G cells generated and maintained mature adhesive junctional domains to which LIN-7 was recruited. Alterations in the junctional domain of U373MG cells were associated with higher motility in a poly-L-lysine migration assay. When the T98G cells were cultured on Matrigel matrix, they acquired invasive properties but, despite unchanged cadherin adhesion system protein levels, the invasive T98G cell-cell contacts failed to accumulate LIN-7 and failed to mature. These results identify the LIN-7 PDZ protein as a marker of cell adhesion maturity and cell invasion and indicate that instability and disorganisation of cadherin-mediated junctions rather than reduced expression of cadherin-catenin system components are required to promote migration and invasiveness in glioblastoma cell lines.