nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.03.2015 | Original Article - Cancer Research

Targeting VEGF and interleukin-6 for controlling malignant effusion of primary effusion lymphoma

verfasst von: Hiroki Goto, Eriko Kudo, Ryusho Kariya, Manabu Taura, Harutaka Katano, Seiji Okada

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 3/2015

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma that shows malignant effusion most commonly seen in advanced AIDS patients. In this study, we clarified the potential role of VEGF and IL-6 in PEL fluid retention and evaluated the efficacy of humanized anti-VEGF monoclonal antibody (mAb), bevacizumab, and humanized anti-IL-6 receptor mAb, tocilizumab, against PEL.

Methods

The production of VEGF and IL-6, and the expression of IL-6Rα in PEL cell lines were examined. The antiproliferative effect of bevacizumab and tocilizumab on PEL cells was evaluated in vitro. The effect of tocilizumab on VEGF was also examined. An intraperitoneal xenograft mouse model was used for in vivo efficacy.

Results

Although we found the production of VEGF and IL-6, and the expression of IL-6Rα in PEL cell lines, bevacizumab and tocilizumab did not inhibit the proliferation of PEL cells in vitro. Tocilizumab decreased VEGF mRNA and VEGF production by inhibiting Stat3 phosphorylation and Stat3 binding to VEGF promoter. In a PEL xenograft mouse model that showed profuse ascites, bevacizumab suppressed ascites formation completely, indicating the critical role of VEGF for PEL fluid retention. Tocilizumab also significantly inhibited ascites formation in vivo. Moreover, these mAbs improved the overall survival of treated mice.

Conclusions

IL-6-VEGF axis contributed to fluid retention, and bevacizumab and tocilizumab could be effective molecular targeting therapies for PEL.

Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T (1990) A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J 9(6):1897–1906PubMedCentralPubMed

Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77(1):63–71CrossRefPubMed

Al Zaid Siddiquee K, Turkson J (2008) STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res 18(2):254–267. doi:10.1038/cr.2008.18 CrossRefPubMed

Aoki Y, Tosato G (1999) Role of vascular endothelial growth factor/vascular permeability factor in the pathogenesis of Kaposi’s sarcoma-associated herpesvirus-infected primary effusion lymphomas. Blood 94(12):4247–4254PubMed

Aoki Y, Jaffe ES, Chang Y, Jones K, Teruya-Feldstein J, Moore PS, Tosato G (1999) Angiogenesis and hematopoiesis induced by Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93(12):4034–4043PubMed

Aoki Y, Narazaki M, Kishimoto T, Tosato G (2001) Receptor engagement by viral interleukin-6 encoded by Kaposi sarcoma-associated herpesvirus. Blood 98(10):3042–3049CrossRefPubMed

Aoki Y, Feldman GM, Tosato G (2003) Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101(4):1535–1542. doi:10.1182/blood-2002-07-2130 CrossRefPubMed

Birx DL, Redfield RR, Tencer K, Fowler A, Burke DS, Tosato G (1990) Induction of interleukin-6 during human immunodeficiency virus infection. Blood 76(11):2303–2310PubMed

Boulanger E, Gerard L, Gabarre J, Molina JM, Rapp C, Abino JF, Cadranel J, Chevret S, Oksenhendler E (2005) Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS. J Clin Oncol 23(19):4372–4380. doi:10.1200/JCO.2005.07.084 CrossRefPubMed

Breen EC, Rezai AR, Nakajima K, Beall GN, Mitsuyasu RT, Hirano T, Kishimoto T, Martinez-Maza O (1990) Infection with HIV is associated with elevated IL-6 levels and production. J Immunol 144(2):480–484PubMed

Castillo JJ, Shum H, Lahijani M, Winer ES, Butera JN (2012) Prognosis in primary effusion lymphoma is associated with the number of body cavities involved. Leuk Lymphoma 53(12):2378–2382. doi:10.3109/10428194.2012.694075 CrossRefPubMed

Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332(18):1186–1191. doi:10.1056/NEJM199505043321802 CrossRefPubMed

Cheranov SY, Karpurapu M, Wang D, Zhang B, Venema RC, Rao GN (2008) An essential role for SRC-activated STAT-3 in 14, 15-EET-induced VEGF expression and angiogenesis. Blood 111(12):5581–5591. doi:10.1182/blood-2007-11-126680 CrossRefPubMedCentralPubMed

Drexler HG, Meyer C, Gaidano G, Carbone A (1999) Constitutive cytokine production by primary effusion (body cavity-based) lymphoma-derived cell lines. Leukemia 13(4):634–640CrossRefPubMed

Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2(10):795–803. doi:10.1038/nrc909 CrossRefPubMed

Goto H, Kariya R, Shimamoto M, Kudo E, Taura M, Katano H, Okada S (2012) Antitumor effect of berberine against primary effusion lymphoma via inhibition of NF-kappaB pathway. Cancer Sci 103(4):775–781. doi:10.1111/j.1349-7006.2012.02212.x CrossRefPubMed

Greene W, Kuhne K, Ye F, Chen J, Zhou F, Lei X, Gao SJ (2007) Molecular biology of KSHV in relation to AIDS-associated oncogenesis. Cancer Treat Res 133:69–127CrossRefPubMedCentralPubMed

Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374(Pt 1):1–20. doi:10.1042/BJ20030407 CrossRefPubMedCentralPubMed

Hong DS, Angelo LS, Kurzrock R (2007) Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 110(9):1911–1928. doi:10.1002/cncr.22999 CrossRefPubMed

Keller SA, Schattner EJ, Cesarman E (2000) Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96(7):2537–2542PubMed

Kishimoto T (2005) Interleukin-6: from basic science to medicine–40 years in immunology. Annu Rev Immunol 23:1–21. doi:10.1146/annurev.immunol.23.021704.115806 CrossRefPubMed

Klass CM, Krug LT, Pozharskaya VP, Offermann MK (2005) The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production. Blood 105(10):4028–4034. doi:10.1182/blood-2004-09-3569 CrossRefPubMedCentralPubMed

Molden J, Chang Y, You Y, Moore PS, Goldsmith MA (1997) A Kaposi’s sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. J Biol Chem 272(31):19625–19631CrossRefPubMed

Mori Y, Nishimoto N, Ohno M, Inagi R, Dhepakson P, Amou K, Yoshizaki K, Yamanishi K (2000) Human herpesvirus 8-encoded interleukin-6 homologue (viral IL-6) induces endogenous human IL-6 secretion. J Med Virol 61(3):332–335CrossRefPubMed

Mullberg J, Geib T, Jostock T, Hoischen SH, Vollmer P, Voltz N, Heinz D, Galle PR, Klouche M, Rose-John S (2000) IL-6 receptor independent stimulation of human gp130 by viral IL-6. J Immunol 164(9):4672–4677CrossRefPubMed

Nagy JA, Meyers MS, Masse EM, Herzberg KT, Dvorak HF (1995) Pathogenesis of ascites tumor growth: fibrinogen influx and fibrin accumulation in tissues lining the peritoneal cavity. Cancer Res 55(2):369–375PubMed

Nakajima K, Martinez-Maza O, Hirano T, Breen EC, Nishanian PG, Salazar-Gonzalez JF, Fahey JL, Kishimoto T (1989) Induction of IL-6 (B cell stimulatory factor-2/IFN-beta 2) production by HIV. J Immunol 142(2):531–536PubMed

Nicholas J, Zong JC, Alcendor DJ, Ciufo DM, Poole LJ, Sarisky RT, Chiou CJ, Zhang X, Wan X, Guo HG, Reitz MS, Hayward GS (1998) Novel organizational features, captured cellular genes, and strain variability within the genome of KSHV/HHV8. J Natl Cancer Inst Monogr 23:79–88CrossRefPubMed

Osborne J, Moore PS, Chang Y (1999) KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways. Hum Immunol 60(10):921–927CrossRefPubMed

Rieckmann P, Poli G, Kehrl JH, Fauci AS (1991) Activated B lymphocytes from human immunodeficiency virus-infected individuals induce virus expression in infected T cells and a promonocytic cell line, U1. J Exp Med 173(1):1–5CrossRefPubMed

Scala G, Ruocco MR, Ambrosino C, Mallardo M, Giordano V, Baldassarre F, Dragonetti E, Quinto I, Venuta S (1994) The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein. J Exp Med 179(3):961–971CrossRefPubMed

Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219(4587):983–985CrossRefPubMed

Shih T, Lindley C (2006) Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 28(11):1779–1802. doi:10.1016/j.clinthera.2006.11.015 CrossRefPubMed

Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, Rosean TR, Klapper W, Tosato G, Janz S, Scheller J, Rose-John S (2012) HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood 119(22):5173–5181. doi:10.1182/blood-2011-09-377705 CrossRefPubMedCentralPubMed

Tanaka T, Narazaki M, Kishimoto T (2012) Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 52:199–219. doi:10.1146/annurev-pharmtox-010611-134715 CrossRefPubMed

Toomey NL, Deyev VV, Wood C, Boise LH, Scott D, Liu LH, Cabral L, Podack ER, Barber GN, Harrington WJ Jr (2001) Induction of a TRAIL-mediated suicide program by interferon alpha in primary effusion lymphoma. Oncogene 20(48):7029–7040. doi:10.1038/sj.onc.1204895 CrossRefPubMed

Trikha M, Corringham R, Klein B, Rossi JF (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9(13):4653–4665PubMedCentralPubMed

Wu W, Rochford R, Toomey L, Harrington W Jr, Feuer G (2005) Inhibition of HHV-8/KSHV infected primary effusion lymphomas in NOD/SCID mice by azidothymidine and interferon-alpha. Leuk Res 29(5):545–555. doi:10.1016/j.leukres.2004.11.010 CrossRefPubMed

Titel: Targeting VEGF and interleukin-6 for controlling malignant effusion of primary effusion lymphoma
verfasst von: Hiroki Goto
Eriko Kudo
Ryusho Kariya
Manabu Taura
Harutaka Katano
Seiji Okada
Publikationsdatum: 01.03.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 3/2015
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-014-1842-9

Springer Medizin

Targeting VEGF and interleukin-6 for controlling malignant effusion of primary effusion lymphoma