To test the expression level of CD40 on ovarian cancer tissues and its correlation to clinicopathological features of patients and to evaluate the therapeutic effectiveness of adenovirus-mediated CD40 ligand on ovarian cancer in vitro.
Material and Methods
The expression of CD40 on paraffin-embedded ovarian cancer tissues (n = 58) and normal ovarian tissues (n = 15) was tested by immunohistochemistry, and CD40 expression on ovarian cancer cells derived from fresh surgical specimens was tested by flow cytometry analysis. The apoptosis-inducing effects of adenovirus-mediated CD40 ligand therapy on ovarian cancer cells derived from fresh surgical specimens were analyzed by flow cytometry analysis and TUNEL assay.
Results
CD40 expression was detected in 60.3% (35/58) of paraffin-embedded ovarian cancer tissues and 73.3% (11/15) of fresh ovarian cancer tissues, but not in normal ovarian tissues (n = 15). CD40 expression was significantly correlated with FIGO stage of ovarian cancer. Adenovirus-mediated CD40 ligand therapy induced significant apoptosis effects on ovarian cancer cells derived from fresh surgical specimens in vitro compared to null adenovirus vector and phosphate-buffered saline.
Conclusions
Our results suggested the therapeutic potential of adenovirus-mediated CD40 ligand on ovarian cancer, especially on the late stage of ovarian cancer.
BrewerM.A., JohnsonK., FollenM., GershensonD., BastR.Jr.: Prevention of ovarian cancer: intraepithelial neoplasia.Clin Cancer Res, 9: 20–30, 2003.
2.
van KootenC., BanchereauJ.: CD40-CD40 ligand.J Leuk Biol, 67: 2–17, 2000.
3.
QuezadaS.A., JarvinenL.Z., LindE.F., NoelleR.J.: CD40/CD154 interactions at the interface of tolerance and immunity.Annu Rev Immunol, 22: 307–328, 2004.
4.
ThomasW.D., SmithM.J., SiZ, HerseyP.: Expression of the co-stimulatory molecule CD40 on melanoma cells.Int J Cancer, 68: 795–801, 1996.
5.
HillS.C., YoudeS.J., ManS., TealeG.R., BaxendaleA.J., HislopA., DaviesC.C., LuesleyD.M., BlomA.M., RickinsonA.B., YoungL.S., EliopoulosA.G.: Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis.J Immunol, 174: 41–50, 2005.
6.
HiranoA., LongoD.L., TaubD.D., FerrisD.K., YoungL.S., EliopoulosA.G., AgathanggelouA., CullenN., MacartneyJ., FanslowW.C., MurphyW.J.: Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand.Blood, 93: 2999–3007, 1999.
TongA.W., StoneM.J.: Prospects for CD40-directed experimental therapy of human cancer.Cancer Gene Ther, 10: 1–13, 2003.
10.
SzocinskiJ.L., KhaledA.R., HixonJ., HalversonD., FunakoshiS., FanslowWC., BoydA., TaubD.D., DurumS.K., SiegallC.B., LongoD.L., MurphyW.J.: Activation-induced cell death of aggressive histology lymphomas by CD40 stimulation: induction of bax.Blood, 100: 217–223, 2002.
11.
DallmanC., JohnsonP.W., PackhamG.: Differential regulation of cell survival by CD40.Apoptosis, 8: 45–53, 2003.
12.
TongA.W., PapayotiM.H., NettoG., ArmstrongD.T., OrdonezG., LawsonJ.M., StoneM.J.: Growth-inhibitory effects of CD40 ligand (CD154) and its endogenous expression in human breast cancer.Clin Cancer Res, 7: 691–703, 2001.
13.
BussolatiB., RussoS., DeambrosisI., CantaluppiV., VolpeA., FerrandoU., CamussiG.: Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet-activating factor synthesis.Int J Cancer, 100: 654–661, 2002.
14.
VestalR.E., WingettD.G., KnightL.K., StillingerR.A., CantorG.H., NielsonC.P., FanslowW.C., GhalieR.: Expression of CD40 in breast, colon, lung, and ovarian tumors.Proc Am Assoc Cancer Res, 38: A1550 (Abstract), 1997.
15.
CiaravinoG., BhatM., ManbeianC.A., TengN.N.: Differential expression of CD40 and CD95 in ovarian carcinoma.Eur J Gynaecol Oncol, 25: 27–32, 2004.
16.
PammerJ., WeningerW., MazalP.R., HorvatR., TschachlerE.: Expression of the CD40 antigen on normal endothelial cells and in benign and malignant tumours of vascular origin.Histopathology, 29: 517–524, 1996.
DzojicH., LoskogA., TottermanT.H., EssandM.: Adenovirus-mediated CD40 ligand therapy induces tumor cell apoptosis and systemic immunity in the TRAMP-C2 mouse prostate cancer model.Prostate, 66: 831–838, 2006.
19.
KikuchiT., MiyazawaN., MooreM.A., CrystalR.G.: Tumor regression induced by intratumor administration of adenovirus vector expressing CD40 ligand and naive dendritic cells.Cancer Res, 60: 6391–6395, 2000.
20.
YoungLS., EliopoulosAG., GallagherNJ., DawsonC.W.: CD40 and epithelial cells: across the great divide.Immunol Today, 19: 502–506, 1998.
21.
GhamandeS., HylanderB.L., OflazogluE., LeleS., FanslowW., RepaskyE.A.: Recombinant CD40 ligand therapy has significant antitumor effects on CD40–positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin.Cancer Res, 61: 7556–7562, 2001.
22.
BugajskaU., GeorgopoulosN.T., SouthgateJ., JohnsonP.W., GraberP., GordonJ., SelbyP.J., TrejdosiewiczL.K.: The effects of malignant transformation on susceptibility of human urothelial cells to CD40-mediated apoptosis.J Natl Cancer Inst, 94: 1381–1395, 2002.
23.
EliopoulosA.G., DaviesC., KnoxPG., GallagherN.J., AffordS.C., AdamsD.H., YoungL.S.: CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily.Mol Cell Biol, 20: 5503–5515, 2000.
24.
EliopoulosA.G., YoungL.S.: The role of the CD40 pathway in the pathogenesis and treatment of cancer.Curr Opin Pharmacol, 4: 360–367, 2004.
25.
FrumanD.A., SnapperS.B., YballeC.M., DavidsonL., YuJ.Y., AltF.W., CantleyL.C.: Impaired B cell development and proliferation in the absence of phosphoinositide 3-kinase p85 alpha.Science, 283: 393–397, 1999.
26.
SchliengerK., ChuC.S., WooE.Y., RiversP.M., TollA.J., HudsonB., MausM.V., RileyJ.L., ChoiY., CoukosG., KaiserL.R., RubinS.C., LevineB.L., CarrollR.G., JuneC.H.: TRANCE- and CD40 ligand-matured dendritic cells reveal MHC class I-re-stricted T cells specific for autologous tumor in late-stage ovarian cancer patients.Clin Cancer Res, 9: 1517–1527, 2003.
