nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

06.09.2016 | Original Article – Cancer Research

Inhibition of fatty acid synthase suppresses neovascularization via regulating the expression of VEGF-A in glioma

verfasst von: Yiqiang Zhou, Guishan Jin, Ruifang Mi, Junwen Zhang, Jin Zhang, Hengzhou Xu, Sen Cheng, Yunsheng Zhang, Wenjie Song, Fusheng Liu

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 12/2016

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Fatty acids (FAs) are essential for membrane lipids biosynthesis and energy consumption in cancer cells. De novo FAs synthesis is catalyzed by fatty acid synthase (FASN), which is overexpressed and correlates with histological grade in glioma. Herein, we focused on the role of FASN in glioma neovascularization.

Methods

The expression levels of FASN, Ki67 and CD34 were determined using immunohistochemistry (IHC). FASN specific-targeted shRNA and C75 were applied to evaluate the influence of FASN on glioma stem cell proliferation, migration and tube formation ability in vitro. An intracranial glioma model was established to study the effects of FASN on tumor growth and neovascularization in vivo.

Results

IHC staining showed that the expression level of FASN correlated with tumor grade, Ki67 levels and microvessels density (MVD) in human gliomas. Inhibition of FASN using shRNAs or C75 decreased tumor growth, prolonged the overall survival of xenograft mice and decreased MVD in brain tumor sections. Moreover, inhibition of FASN blocked hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGF-A) signaling and upregulated the anti-angiogenic isoform-VEGF₁₆₅b.

Conclusion

Our results suggest that FASN plays a pivotal role in glioma neovascularization, and inhibition of FASN may be a potential target for anti-angiogenic therapy for glioma.

Nur mit Berechtigung zugänglich

Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP (2005) Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 24:39–46. doi:10.1038/sj.onc.1208174 CrossRefPubMed

Bian Y, Yu Y, Wang S, Li L (2015) Up-regulation of fatty acid synthase induced by EGFR/ERK activation promotes tumor growth in pancreatic cancer. Biochem Biophys Res Commun 463:612–617. doi:10.1016/j.bbrc.2015.05.108 CrossRefPubMed

Bottini A, Berruti A, Bersiga A, Brizzi MP, Allevi G, Bolsi G, Aguggini S, Brunelli A, Betri E, Generali D, Scaratti L, Bertoli G, Alquati P, Dogliotti L (2002) Changes in microvessel density as assessed by CD34 antibodies after primary chemotherapy in human breast cancer. Clin Cancer Res 8:1816–1821PubMed

Browne CD, Hindmarsh EJ, Smith JW (2006) Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. FASEB J 20:2027–2035. doi:10.1096/fj.05-5404com CrossRefPubMed

Camassei FD, Cozza R, Acquaviva A, Jenkner A, Rava L, Gareri R, Donfrancesco A, Bosman C, Vadala P, Hadjistilianou T, Boldrini R (2003) Expression of the lipogenic enzyme fatty acid synthase (FAS) in retinoblastoma and its correlation with tumor aggressiveness. Invest Ophthalmol Vis Sci 44:2399–2403. doi:10.1002/mpo.10274 CrossRefPubMed

Grube S, Dunisch P, Freitag D, Klausnitzer M, Sakr Y, Walter J, Kalff R, Ewald C (2014) Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with Orlistat reduces cell viability and triggers apoptosis. J Neurooncol 118:277–287. doi:10.1007/s11060-014-1452-z CrossRefPubMed

Hochachka PW, Rupert JL, Goldenberg L, Gleave M, Kozlowski P (2002) Going malignant: the hypoxia-cancer connection in the prostate. BioEssays 24:749–757. doi:10.1002/bies.10131 CrossRefPubMed

Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW (2004) Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res 64:2070–2075CrossRefPubMed

Kuhajda FP (2000) Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16:202–208CrossRefPubMed

Lal S, Lacroix M, Tofilon P, Fuller GN, Sawaya R, Lang FF (2000) An implantable guide-screw system for brain tumor studies in small animals. J Neurosurg 92:326–333. doi:10.3171/jns.2000.92.2.0326 CrossRefPubMed

Li JN, Gorospe M, Chrest FJ, Kumaravel TS, Evans MK, Han WF, Pizer ES (2001) Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res 61:1493–1499PubMed

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131:803–820. doi:10.1007/s00401-016-1545-1 CrossRefPubMed

Macarthur KM, Kao GD, Chandrasekaran S, Alonso-Basanta M, Chapman C, Lustig RA, Wileyto EP, Hahn SM, Dorsey JF (2014) Detection of brain tumor cells in the peripheral blood by a telomerase promoter-based assay. Cancer Res 74:2152–2159. doi:10.1158/0008-5472.CAN-13-0813 CrossRefPubMedPubMedCentral

Mao XG, Xue XY, Wang L, Zhang X, Yan M, Tu YY, Lin W, Jiang XF, Ren HG, Zhang W, Song SJ (2013) CDH5 is specifically activated in glioblastoma stemlike cells and contributes to vasculogenic mimicry induced by hypoxia. Neuro Oncol 15:865–879. doi:10.1093/neuonc/not029 CrossRefPubMedPubMedCentral

Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763–777. doi:10.1038/nrc2222 CrossRefPubMed

Menendez JA, Vellon L, Oza BP, Lupu R (2005) Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1alpha (HIF-1alpha)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing her-2/neu oncogene. J Cell Biochem 94:857–863. doi:10.1002/jcb.20367 CrossRefPubMed

Peiris-Pages M (2012) The role of VEGF 165b in pathophysiology. Cell Adhes Migr 6:561–568. doi:10.4161/cam.22439 CrossRef

Pizer ES, Jackisch C, Wood FD, Pasternack GR, Davidson NE, Kuhajda FP (1996) Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res 56:2745–2747PubMed

Pizer ES, Chrest FJ, DiGiuseppe JA, Han WF (1998) Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res 58:4611–4615PubMed

Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111. doi:10.1038/35102167 CrossRefPubMed

Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–828. doi:10.1038/nature09557 CrossRefPubMed

Seguin F, Carvalho MA, Bastos DC, Agostini M, Zecchin KG, Alvarez-Flores MP, Chudzinski-Tavassi AM, Coletta RD, Graner E (2012) The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas. Br J Cancer 107:977–987. doi:10.1038/bjc.2012.355 CrossRefPubMedPubMedCentral

Soda Y, Marumoto T, Friedmann-Morvinski D, Soda M, Liu F, Michiue H, Pastorino S, Yang M, Hoffman RM, Kesari S, Verma IM (2011) Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci USA 108:4274–4280. doi:10.1073/pnas.1016030108 CrossRefPubMedPubMedCentral

Tao BB, He H, Shi XH, Wang CL, Li WQ, Li B, Dong Y, Hu GH, Hou LJ, Luo C, Chen JX, Chen HR, Yu YH, Sun QF, Lu YC (2013) Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade. J Clin Neurosci 20:717–720. doi:10.1016/j.jocn.2012.03.050 CrossRefPubMed

Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, Buckley D, Kemble G, Heuer TS (2015) Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine 2:808–824. doi:10.1016/j.ebiom.2015.06.020 CrossRefPubMedPubMedCentral

Wakamiya T, Suzuki SO, Hamasaki H, Honda H, Mizoguchi M, Yoshimoto K, Iwaki T (2014) Elevated expression of fatty acid synthase and nuclear localization of carnitine palmitoyltransferase 1C are common among human gliomas. Neuropathology 34:465–474. doi:10.1111/neup.12132 CrossRefPubMed

Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468:829–833. doi:10.1038/nature09624 CrossRefPubMed

Ward RJ, Dirks PB (2007) Cancer stem cells: at the headwaters of tumor development. Annu Rev Pathol 2:175–189. doi:10.1146/annurev.pathol.2.010506.091847 CrossRefPubMed

Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507. doi:10.1056/NEJMra0708126 CrossRefPubMed

Yasumoto Y, Miyazaki H, Vaidyan LK, Kagawa Y, Ebrahimi M, Yamamoto Y, Ogata M, Katsuyama Y, Sadahiro H, Suzuki M, Owada Y (2016) Inhibition of fatty acid synthase decreases expression of stemness markers in glioma stem cells. PLoS ONE 11:e0147717. doi:10.1371/journal.pone.0147717 CrossRefPubMedPubMedCentral

Zaytseva YY, Rychahou PG, Gulhati P, Elliott VA, Mustain WC, O’Connor K, Morris AJ, Sunkara M, Weiss HL, Lee EY, Evers BM (2012) Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res 72:1504–1517. doi:10.1158/0008-5472.CAN-11-4057 CrossRefPubMedPubMedCentral

Zaytseva YY, Elliott VA, Rychahou P, Mustain WC, Kim JT, Valentino J, Gao T, O’Connor KL, Neltner JM, Lee EY, Weiss HL, Evers BM (2014) Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer. Carcinogenesis 35:1341–1351. doi:10.1093/carcin/bgu042 CrossRefPubMedPubMedCentral

Zhao Y, Dong J, Huang Q, Lou M, Wang A, Lan Q (2010) Endothelial cell transdifferentiation of human glioma stem progenitor cells in vitro. Brain Res Bull 82:308–312. doi:10.1016/j.brainresbull.2010.06.006 CrossRefPubMed

Zhou W, Han WF, Landree LE, Thupari JN, Pinn ML, Bililign T, Kim EK, Vadlamudi A, Medghalchi SM, El Meskini R, Ronnett GV, Townsend CA, Kuhajda FP (2007) Fatty acid synthase inhibition activates AMP-activated protein kinase in SKOV3 human ovarian cancer cells. Cancer Res 67:2964–2971. doi:10.1158/0008-5472.CAN-06-3439 CrossRefPubMed

Zhou Y, Jin G, Mi R, Dong C, Zhang J, Liu F (2014) The methylation status of the platelet-derived growth factor-B gene promoter and its regulation of cellular proliferation following folate treatment in human glioma cells. Brain Res 1556:57–66. doi:10.1016/j.brainres.2014.01.045 CrossRefPubMed

Titel: Inhibition of fatty acid synthase suppresses neovascularization via regulating the expression of VEGF-A in glioma
verfasst von: Yiqiang Zhou
Guishan Jin
Ruifang Mi
Junwen Zhang
Jin Zhang
Hengzhou Xu
Sen Cheng
Yunsheng Zhang
Wenjie Song
Fusheng Liu
Publikationsdatum: 06.09.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 12/2016
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-016-2249-6

Springer Medizin

Inhibition of fatty acid synthase suppresses neovascularization via regulating the expression of VEGF-A in glioma