Top

Published in:

01-06-2009 | Research Paper

NK4, an HGF antagonist, prevents hematogenous pulmonary metastasis by inhibiting adhesion of CT26 cells to endothelial cells

Authors: Takeshi Kubota, Hiroaki Taiyoh, Atsushi Matsumura, Yasutoshi Murayama, Daisuke Ichikawa, Kazuma Okamoto, Hitoshi Fujiwara, Hisashi Ikoma, Masayoshi Nakanishi, Shojiro Kikuchi, Chouhei Sakakura, Toshiya Ochiai, Yukihito Kokuba, Hiroki Taniguchi, Teruhisa Sonoyama, Kunio Matsumoto, Toshikazu Nakamura, Eigo Otsuji

Published in: Clinical & Experimental Metastasis | Issue 5/2009

Abstract

Hepatocyte growth factor (HGF) plays a definitive role in invasive, angiogenic, and metastatic activities of tumor cells by binding to the c-Met receptor. NK4, a competitive antagonist for HGF and the c-Met receptor, prevents tumor cell growth and metastasis via its bifunctional properties to act as an HGF antagonist and angiogenesis inhibitor. In the present study, we investigated the inhibitory effectiveness of NK4 on hematogenous pulmonary metastasis of the CT26 murine colon cancer cell line, focusing on tumor cell adhesion to endothelial cells. In an in vitro adhesion assay, HGF facilitated adhesion of CT26 cells to a murine endothelial cell line (F-2) in a dose-dependent manner. Furthermore, the enhancing effect of HGF on CT26-F-2 cell interaction was blocked by NK4 as well as by anti-HGF antibody. Similarly, HGF-induced phosphorylation of focal adhesion kinase (FAK), downstream of integrin signaling, was reduced by NK4 and by anti-HGF antibody. However, distinct integrin expression on the surface of CT26 cells was not altered by HGF. In an in vivo experimental pulmonary metastasis assay, stable NK4 expression potently decreased the number of pulmonary metastatic foci. The NK4-induced suppression of pulmonary metastasis was partially reversed when HGF was intraperitoneally administered in an adhesive phase. These results suggest that NK4 could act on tumor cells to inhibit CT26 adhesion to endothelial cells by reducing FAK phosphorylation, which is regulated by inside-out HGF/c-Met signaling, and thereby suppress hematogenous pulmonary metastasis.

Nakamura T, Nishizawa T, Hagiya M et al (1989) Molecular cloning and expression of human hepatocyte growth factor. Nature 342:440–443. doi:10.1038/342440a0 PubMedCrossRef

Miyazawa K, Tsubouchi H, Naka D et al (1989) Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun 163:967–973. doi:10.1016/0006-291X(89)92316-4 PubMedCrossRef

Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925. doi:10.1038/nrm1261 PubMedCrossRef

Jiang WG, Martin TA, Parr C, Davies G, Matsumoto K, Nakamura T (2005) Hepatocyte growth factor, its receptor, and their potential value in cancer therapies. Crit Rev Oncol Hematol 53:35–69. doi:10.1016/j.critrevonc.2004.09.004 PubMedCrossRef

Matsumoto K, Nakamura T (1996) Emerging multipotent aspects of hepatocyte growth factor. J Biochem 119:591–600PubMed

Fazekas K, Csuka O, Koves I, Raso E, Timar J (2000) Experimental and clinicopathologic studies on the function of the HGF receptor in human colon cancer metastasis. Clin Exp Metastasis 18:639–649. doi:10.1023/A:1013136303880 PubMedCrossRef

Otte JM, Schmitz F, Kiehne K et al (2000) Functional expression of HGF and its receptor in human colorectal cancer. Digestion 61:237–246. doi:10.1159/000007764 PubMedCrossRef

Date K, Matsumoto K, Shimura H, Tanaka M, Nakamura T (1997) HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett 420:1–6. doi:10.1016/S0014-5793(97)01475-0 PubMedCrossRef

Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M, Nakamura T (2000) HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res 60:6737–6743PubMed

10.

Matsumoto K, Nakamura T (2005) Mechanism and significance of bifunctional NK4 in cancer treatment. Biochem Biophys Res Commun 333:316–327. doi:10.1016/j.bbrc.2005.05.131 PubMedCrossRef

11.

Fujiwara H, Kubota T, Amaike H et al (2005) Suppression of peritoneal implantation of gastric cancer cells by adenovirus vector-mediated NK4 expression. Cancer Gene Ther 12:206–216. doi:10.1038/sj.cgt.7700782 PubMedCrossRef

12.

Yoshimura M, Fujiwara H, Kubota T et al (2005) Possible inhibition of cancer cell adhesion to the extracellular matrix in NK4-induced suppression of peritoneal implantation. Anticancer Res 25:3847–3854PubMed

13.

Kubota T, Fujiwara H, Amaike H et al (2004) Reduced HGF expression in subcutaneous CT26 tumor genetically modified to secrete NK4 and its possible relation with antitumor effects. Cancer Sci 95:321–327. doi:10.1111/j.1349-7006.2004.tb03210.x PubMedCrossRef

14.

Kushibiki T, Matsumoto K, Nakamura T, Tabata Y (2004) Suppression of tumor metastasis by NK4 plasmid DNA released from cationized gelatin. Gene Ther 11:1205–1214. doi:10.1038/sj.gt.3302285 PubMedCrossRef

15.

Saimura M, Nagai E, Mizumoto K et al (2002) Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4. Clin Cancer Res 8:3243–3249PubMed

16.

Voura EB, Sandig M, Siu CH (1998) Cell–cell interactions during transendothelial migration of tumor cells. Microsc Res Tech 43:265–275. doi:10.1002/(SICI)1097-0029(19981101)43:3<265::AID-JEMT9>3.0.CO;2-Z PubMedCrossRef

17.

Honn KV, Tang DG (1992) Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix. Cancer Metastasis Rev 11:353–375. doi:10.1007/BF01307187 PubMedCrossRef

18.

Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25. doi:10.1016/0092-8674(92)90115-S PubMedCrossRef

19.

Price EA, Coombe DR, Murray JC (1996) Beta-1 integrins mediate tumour cell adhesion to quiescent endothelial cells in vitro. Br J Cancer 74:1762–1766PubMed

20.

Weimar IS, de Jong D, Muller EJ et al (1997) Hepatocyte growth factor/scatter factor promotes adhesion of lymphoma cells to extracellular matrix molecules via alpha 4 beta 1 and alpha 5 beta 1 integrins. Blood 89:990–1000PubMed

21.

Trusolino L, Cavassa S, Angelini P et al (2000) HGF/scatter factor selectively promotes cell invasion by increasing integrin avidity. FASEB J 14:1629–1640. doi:10.1096/fj.14.11.1629 PubMedCrossRef

22.

Sieg DJ, Hauck CR, Schlaepfer DD (1999) Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci 112:2677–2691PubMed

23.

Matsumoto K, Matsumoto K, Nakamura T, Kramer R (1994) Hepatocyte growth factor/scatter factor induces tyrosine phosphorylation of focal adhesion kinase (p125 FAK) and promotes migration and invasion by oral squamous cell carcinoma cells. J Biol Chem 269:31807–31813PubMed

24.

Chen HC, Chan PC, Tang MJ, Cheng CH, Chang TJ (1998) Tyrosine phosphorylation of focal adhesion kinase stimulated by hepatocyte growth factor leads to mitogen-activated protein kinase activation. J Biol Chem 273:25777–25782. doi:10.1074/jbc.273.40.25777 PubMedCrossRef

25.

Van Slambrouck S, Grijelmo C, De Wever O et al (2007) Activation of the FAK-src molecular scaffolds and p130Cas-JNK signaling cascades by alpha1-integrins during colon cancer cell invasion. Int J Oncol 31:1501–1508PubMed

26.

von Wichert G, Krndija D, Schmid H et al (2008) Focal adhesion kinase mediates defects in the force-dependent reinforcement of initial integrin-cytoskeleton linkages in metastatic colon cancer cell lines. Eur J Cell Biol 87:1–16. doi:10.1016/j.ejcb.2007.07.008

27.

Toda K, Tsujioka K, Maruguchi Y et al (1990) Establishment and characterization of a tumorigenic murine vascular endothelial cell line (F-2). Cancer Res 50:5526–5530PubMed

28.

Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13:555–562. doi:10.1016/S0955-0674(00)00251-9 PubMedCrossRef

29.

Chambers AF, MacDonald IC, Schmidt EE et al (1995) Steps in tumor metastasis: new concepts from intravital videomicroscopy. Cancer Metastasis Rev 14:279–301. doi:10.1007/BF00690599 PubMedCrossRef

30.

Fidler IJ (1990) Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 50:6130–6138PubMed

31.

Bussolino F, Di Renzo MF, Ziche M et al (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119:629–641. doi:10.1083/jcb.119.3.629 PubMedCrossRef

32.

Davies G, Jiang WG, Mason MD (2001) Matrilysin mediates extracellular cleavage of E-Cadherin from prostate cancer cells. A key mechanism in hepatocyte growth factor/scatter factor-induced cell–cell dissociation and in vitro invasion. Clin Cancer Res 7:3289–3297PubMed

33.

Nakamura Y, Matsubara D, Goto A et al (2008) Constitutive activation of c-Met is correlated with c-Met overexpression and dependent on cell-matrix adhesion in lung adenocarcinoma cell lines. Cancer Sci 99:14–22. doi:10.1111/j.1349-7006.2008.00838.x PubMedCrossRef

34.

Clark EA, Brugge JS (1995) Integrins and signal transduction pathways: the road taken. Science 268:233–239. doi:10.1126/science.7716514 PubMedCrossRef

35.

Beviglia L, Kramer RH (1999) HGF induces FAK activation and integrin-mediated adhesion in MTLn3 breast carcinoma cells. Int J Cancer 83:640–649. doi:10.1002/(SICI)1097-0215(19991126)83:5<640::AID-IJC13>3.0.CO;2-D PubMedCrossRef

36.

Maulik G, Kijima T, Ma PC et al (2002) Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res 8:620–627PubMed

37.

Thamilsevan V, Craig DH, Basson MD (2007) FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3K/Akt pathway. FASEB J 21:1730–1741. doi:10.1096/fj.06-6545com CrossRef

38.

Frisch SM, Francis H (1994) Disruption of epithelial cell–matrix interactions induces apoptosis. J Cell Biol 124:619–626. doi:10.1083/jcb.124.4.619 PubMedCrossRef

39.

Zhang Y, Lu H, Dazin P, Kapila Y (2004) Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: fibronectin and integrin alphav mediate survival signals through focal adhesion kinase. J Biol Chem 279:48342–48349. doi:10.1074/jbc.M407953200 PubMedCrossRef

40.

Kanayama S, Yamada Y, Kawaguchi R, Tsuji Y, Haruta S, Kobayashi H (2008) Hepatocyte growth factor induces anoikis resistance by up-regulation of cyclooxygenase-2 expression in uterine endometrial cancer cells. Oncol Rep 19:117–122PubMed

Title: NK4, an HGF antagonist, prevents hematogenous pulmonary metastasis by inhibiting adhesion of CT26 cells to endothelial cells
Authors: Takeshi Kubota
Hiroaki Taiyoh
Atsushi Matsumura
Yasutoshi Murayama
Daisuke Ichikawa
Kazuma Okamoto
Hitoshi Fujiwara
Hisashi Ikoma
Masayoshi Nakanishi
Shojiro Kikuchi
Chouhei Sakakura
Toshiya Ochiai
Yukihito Kokuba
Hiroki Taniguchi
Teruhisa Sonoyama
Kunio Matsumoto
Toshikazu Nakamura
Eigo Otsuji
Publication date: 01-06-2009
Publisher: Springer Netherlands
Published in: Clinical & Experimental Metastasis / Issue 5/2009
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-009-9244-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2009

Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature

Inhibition of cyclooxygenase-2 suppresses the invasiveness of oral squamous cell carcinoma cell lines via down-regulation of matrix metalloproteinase-2 production and activation

Des-γ-carboxy prothrombin stimulates human vascular endothelial cell growth and migration

Pulmonary lymphangitic sarcomatosis and a review of the literature

Dietary stearate reduces human breast cancer metastasis burden in athymic nude mice

Transient RNA silencing of tissue factor pathway inhibitor-2 modulates lung cancer cell invasion

Keynote webinar | Spotlight on antibody–drug conjugates in cancer