Placenta growth factor (PlGF) is a key regulator of pathological angiogenesis and its overexpression has been linked to neoplastic progression. To assess whether PlGF could have a role in malignant mesothelioma (MM), we analyzed the expression of PlGF, VEGF, and their cognate receptors (VEGF-R1 and VEGF-R2) and co-receptors (neuropilin-1 and neuropilin-2) in MM cell lines as well as in resected MM tissues, hyperplastic/reactive mesothelium and normal mesothelium. MM cell cultures expressed both ligands and the associated receptors to a variable extent and released different amounts of PlGF. As assessed by immunohistochemistry, PlGF expression was switched on in hyperplastic/reactive compared to normal mesothelium. Moreover, 74 and 94% of MM tissues overexpressed PlGF and VEGF-R1, respectively (p<0.05 MM vs normal mesothelium). Administration of recombinant PlGF-2 did not elicit a significant stimulation of MM cell growth, while it was associated with a transient phosphorylation of Akt, suggesting that PlGF-2 could activate downstream effectors of proliferative and cytoprotective signals via VEGF-R1 in MM cells. Indeed, the administration of an anti-PlGF antibody was found to cause a significant reduction of MM cell survival. In conclusion, our data demonstrate that, by acting as a survival factor, PlGF can play a role which goes beyond the stimulation of angiogenesis in MM. This evidence could help the rational design of new therapeutic interventions for this aggressive tumor.
TammelaTEnholmBAlitaloKPaavonenK. The biology of vascular endothelial growth factors. Cardiovasc Res2005; 65:550–63.
5.
De FalcoSGiganteBPersicoMG. Structure and function of placental growth factor. Trends Cardiovasc Med2002; 12:241–6.
6.
ClaussMWeichHBreierGKniesURocklWWaltenbergerJRisauW. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implication for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem1996; 271:17692–734.
7.
AdiniAKornagaTFiroozbakhtFBenjaminLE. Placenta growth factor is a survival factor for human endothelial cells and macrophages. Cancer Res2002; 62:2749–52.
8.
MaglioneDGuerrieroVVigliettoG. Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene1993; 8:925–31.
9.
CaoYJiWRQiPRosinA. Placenta growth factor: Identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun1997; 235:493–8.
10.
ParkJChenHHWinerJHouckKAFerraraN. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vivo and in vitro, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem1994; 269:25646–54.
11.
MigdalMHuppertzBTesslerSComfortiAShibuyaMReichRBaumannHNeufeldG. Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem1998; 273:22272–78.
12.
MamlukRGechtmanZKutcherMEGasiunasNGallagherJKlagsbrunM. Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2 and heparin via its b1b2 domain. J Biol Chem2002; 277:24818–25.
13.
CaoYChenHZhouL. Heterodimers of placenta growth factor/vascular endothelial growth factor. Endothelial activity, tumor cell expression, and high affinity binding to Flk-1/KDR. J Biol Chem1996; 271:3154–62.
14.
AutieroMWaltenbergerJCommuniD. Role of PlGF in the intra- and intermolecular cross-talk between the VEGF receptors Fit-1 and Flk-1. Nat Med2003; 9:936–43.
15.
CarmelietPMoonsLLuttunA. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med2001; 7:575–83.
16.
FisherCMazzoneMJonckxBCarmelietP. FLTl and its ligands VEGFB and PlGF: Drug targets for anti-angiogenic therapy?Nat Rev Cancer2008; 8:942–56.
LuttunABrusselmansKFukaoH. Loss of placenta growth factor protects mice against vascular permeability in pathological conditions. Biochem Biophys Res Commun2002; 295:428–34.
19.
ChenCNHsiehFJChengYMChengWFSuYNChangKJLeePH. The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett2004; 213:73–82.
20.
WeiS-CTsaoP-NYuS-CShunC-TTsai-WuJ-JWuCHHSuY-NHsiehF-JWongJM. Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut2005; 54:666–72.
21.
ParrCWatkinsGBoultonMCaiJJiangWG. Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer2005; 41:2819–27.
22.
MarcelliniMDe LucaNRiccioniT. Increased melanoma growth and metastasis spreading in mice overexpressing placenta growth factor. Am J Pathol2006; 169:643–54.
23.
FisherCJonckxBMazzoneM. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell2007; 131:463–75.
24.
CaoYLindenPShimaDBrowneFFolkmanJ. In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor. J Clin Invest1996; 98:2507–11.
25.
ErikssonACaoRPawliukR. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. Cancer Cell2002; 1:99–108.
26.
XuLCochranDMTongRTWinklerFKashiwagiSJainRKFukumuraD. Placenta growth factor overexpression inhibits tumor growth, angiogenesis and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res2006; 66:3971–7.
27.
SchomberTKopfsteinLDjonovVAlbrechtIBaeriswylVStrittmatterKChristoforiG. Placenta growth factor-1 attenuates vascular endothelial growth factor-A-dependent tumor angiogenesis during â cell carcinogenesis. Cancer Res2007; 67:10840–8.
28.
PassHStevensEJOieH. Characteristic of nine newly derived mesothelioma cell lines. Ann Thor Surg1995; 2:214–20.
29.
OrengoAMSpoletiniLProcopioA. Establishment of four new mesothelioma cell lines: Characterization by ultrastructural and immunophenotypic analysis: Eur Respir J1999; 13:527–34.
30.
VersnelMABoutsMJHoogstedenHCvan der KwastTHDelahayeMHagemeijerA. Establishment of human malignant mesothelioma cell lines. Int J Cancer1989; 44:256–60.
31.
BeiRMentucciaDTronoP. Immunity to extracellular matrix antigens is associated with ultrastructural alterations of the stroma and stratified epithelium basement membrane in the skin of Hashimoto's thyroiditis patients. Int J Immunopathol Pharmacol2006; 19:661–74.
32.
ButtkeTMMcCubreyJAOwenTC. Use of an aqueous soluble tetrazolium/formazan assay to measure viability and proliferation of lymphokine-dependent cell lines. J Immunol Methods1993; 157:233–40.
33.
NishiJMinaminoTMiyauchiH. Vascular endothelial growth factor receptor-1 regulates postnatal angiogenesis through inhibition of the excessive activation of Akt. Circ Res2008; 103:261–8.
34.
MarinoMAcconciaFTrentalanceA. Biphasic estradiol-induced Akt phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. Mol Biol Cell2003; 14:2583–91.
35.
StrizziLCatalanoAVianaleG. Vascular endothelial growth factor is an autocrine growth factor for human malignant mesothelioma. J Pathol2001; 193:468–75.
36.
BielenbergDRPettawayCATakashimaSKlagsbrunM. Neuropilins in neoplasms: Expression, regulation and function. 2005; Exp Cell Res312:584–93.
37.
CianfaraniFZambrunoGBrogelliL. Placenta growth factor in diabetic wound healing: Altered expression and therapeutic potential. Am J Pathol2006; 169:1167–82.
38.
LuttunATjwaMMoonsL. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Fltl. Nat Med2002; 8:831–840.
39.
KerberMReissYWichersheimA. Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer Res2008; 68:7342–51.
40.
PonticelliSMarascoDTaralloV. Modulation of angiogenesis by a tetrameric tripeptide that antagonizes vascular endothelial growth factor receptor 1. J Biol Chem2008; 283:34250–9.
41.
TaylorAPGoldenbergDM. Role of placenta growth factor in malignancy and evidence that an antagonistic PlGF/Flt-1 peptide inhibits the growth and metastasis of human breast cancer xenografts. Mol Cancer Ther2007; 6:524–31.
42.
BarillariGAlboniciLFranzeseO. The basic residues of placenta growth factor type 2 retrieve sequestered angiogenic factors into soluble form. Implication for tumor angiogenesis. Am J Pathol1998; 152:1161–6.
43.
HolmesDIRZacharyI. Placental growth factor induces FosB and c-Fos gene expression via Flt-1 receptors. FEBS Lett2004; 557:93–8.
44.
HeintzNHJanssenYMMossmanBT. Persistent induction of c-fos and c-jun expression by asbestos. Proc Natl Acad Sci1993; 90:3299–303.
45.
Ramos-NinoMETimblinCRMossmanBT. Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression. Cancer Res2002; 62:6065–9.
