Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models
Yuko Kishi
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka;
Present address: Clinical Operations Center, Sanofi-Aventis in Japan, Tokyo, Japan.
Search for more papers by this authorKeiji Kuba
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka;
Division of Molecular Pharmacology and Experimental Therapeutics, Department of Physiology and Pharmacology, Akita University Graduate School of Medicine, Akita;
Search for more papers by this authorTakahiro Nakamura
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;
Search for more papers by this authorJinhua Wen
Peking University Stem Cell Research Center and Cell Biology Department, Peking University Health Science Center, Beijing, China;
Search for more papers by this authorYoshinori Suzuki
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;
Search for more papers by this authorShinya Mizuno
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka;
Search for more papers by this authorToshihiro Nukiwa
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai;
Search for more papers by this authorKunio Matsumoto
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;
Search for more papers by this authorCorresponding Author
Toshikazu Nakamura
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka;
Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, Suita, Osaka, Japan
To whom correspondence should be addressed. E-mail: [email protected]Search for more papers by this authorYuko Kishi
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka;
Present address: Clinical Operations Center, Sanofi-Aventis in Japan, Tokyo, Japan.
Search for more papers by this authorKeiji Kuba
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka;
Division of Molecular Pharmacology and Experimental Therapeutics, Department of Physiology and Pharmacology, Akita University Graduate School of Medicine, Akita;
Search for more papers by this authorTakahiro Nakamura
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;
Search for more papers by this authorJinhua Wen
Peking University Stem Cell Research Center and Cell Biology Department, Peking University Health Science Center, Beijing, China;
Search for more papers by this authorYoshinori Suzuki
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;
Search for more papers by this authorShinya Mizuno
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka;
Search for more papers by this authorToshihiro Nukiwa
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai;
Search for more papers by this authorKunio Matsumoto
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;
Search for more papers by this authorCorresponding Author
Toshikazu Nakamura
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka;
Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, Suita, Osaka, Japan
To whom correspondence should be addressed. E-mail: [email protected]Search for more papers by this authorAbstract
Hepatocyte growth factor (HGF) promotes malignant development of cancer cells by enhancing invasion and metastasis. NK4, a competitive antagonist for HGF, is a bifunctional molecule that acts as a HGF antagonist and angiogenesis inhibitor. Although successful tumor inhibition by NK4 gene expression in tumor models has been demonstrated, the effects of systemic NK4 gene introduction are yet to be addressed. Here we show that systemic administration of a replication-defective adenovirus expressing NK4 (Ad.NK4) inhibits tumor growth and lung metastasis of B16F10 melanoma and Lewis lung carcinoma in syngeneic mice. Single tail-vein injection of Ad.NK4 achieved therapeutic levels of NK4 in the circulation and in multiple organs. Despite NK4 expression that was highest in the liver, toxicity in the liver was minimal. Ad.NK4-mediated growth inhibition was associated with decreased blood vessel density and increased apoptosis in tumor tissues, which suggests that NK4 suppressed tumor growth as an angiogenesis inhibitor. Metastasis of B16F10 melanoma and Lewis lung carcinoma cells to the lung was potently inhibited by systemic Ad.NK4-administration. Our results demonstrated that the adenovirus-mediated induction of high levels of circulating NK4 significantly inhibited in vivo tumor growth and distant metastasis without obvious side effects. NK4 gene therapy is thus a safe and promising strategy for the treatment of cancer patients, and further validation in clinical trials is needed. (Cancer Sci 2009; 100: 1351–1358)
References
- 1 Nakamura T, Nawa K, Ichihara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun 1984; 122: 1450–9.
- 2 Nakamura T, Nishizawa T, Hagiya M et al . Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342: 440–3.
- 3 Funakoshi H, Nakamura T. Hepatocyte growth factor: from diagnosis to clinical applications. Clin Chim Acta 2003; 327: 1–23.
- 4 Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003; 4: 915–25.
- 5 Jiang WG, Martin TA, Parr C, Davies G, Matsumoto K, Nakamura T. Hepatocyte growth factor, its receptor, and their potential value in cancer therapies. Crit Rev Oncol Hematol 2005; 53: 35–69.
- 6 Matsumoto K, Nakamura T. Hepatocyte growth factor and the Met system as a mediator of tumor–stromal interactions. Int J Cancer 2006; 119: 477–83.
- 7 Christensen JG, Schreck R, Burrows J et al . A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 2003; 63: 7345–55.
- 8 Cao B, Su Y, Oskarsson M et al . Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models. Proc Natl Acad Sci USA 2001; 98: 7443–8.
- 9 Michieli P, Mazzone M, Basilico C et al . Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 2004; 6: 61–73.
- 10 Shinomiya N, Gao CF, Xie Q et al . RNA interference reveals that ligand-independent met activity is required for tumor cell signaling and survival. Cancer Res 2004; 64: 7962–70.
- 11 Date K, Matsumoto K, Shimura H, Tanaka M, Nakamura T. HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett 1997; 420: 1–6.
- 12 Date K, Matsumoto K, Kuba K, Shimura H, Tanaka M, Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene 1998; 17: 3045–54.
- 13
Parr C,
Hiscox S,
Nakamura T,
Matsumoto K,
Jiang WG.
NK4, a new HGF/SF variant, is an antagonist to the influence of HGF/SF on the motility and invasion of colon cancer cells.
Int J Cancer
2000; 85: 563–70.
10.1002/(SICI)1097-0215(20000215)85:4<563::AID-IJC19>3.0.CO;2-D CAS PubMed Web of Science® Google Scholar
- 14 Tomioka D, Maehara N, Kuba K et al . Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res 2001; 61: 7518–24.
- 15 Matsumoto K, Nakamura T. Mechanisms and significance of bifunctional NK4 in cancer treatment. Biochem Biophys Res Commun 2005; 333: 316–27.
- 16 Matsumoto K, Nakamura T. NK4 gene therapy targeting HGF-Met and angiogenesis. Front Biosci 2008; 13: 1943–51.
- 17 Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M, Nakamura T. HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res 2000; 60: 6737–43.
- 18 Kuba K, Matsumoto K, Ohnishi K, Shiratsuchi T, Tanaka M, Nakamura T. Kringle 1-4 of hepatocyte growth factor inhibits proliferation and migration of human microvascular endothelial cells. Biochem Biophys Res Commun 2000; 279: 846–52.
- 19 Kuo CJ, Farnebo F, Yu EY et al . Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Proc Natl Acad Sci USA 2001; 98: 4605–10.
- 20 Young LS, Searle PF, Onion D, Mautner V. Viral gene therapy strategies: from basic science to clinical application. J Pathol 2006; 208: 299–318.
- 21 Ogura Y, Mizumoto K, Nagai E et al . Peritumoral injection of adenovirus vector expressing NK4 combined with gemcitabine treatment suppresses growth and metastasis of human pancreatic cancer cells implanted orthotopically in nude mice and prolongs survival. Cancer Gene Ther 2006; 13: 520–9.
- 22 Maemondo M, Narumi K, Saijo Y et al . Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy. Mol Ther 2002; 5: 177–85.
- 23 Saimura M, Nagai E, Mizumoto K et al . Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4. Clin Cancer Res 2002; 8: 3243–9.
- 24 Wen J, Matsumoto K, Taniura N, Tomioka D, Nakamura T. Inhibition of colon cancer growth and metastasis by NK4 gene repetitive delivery in mice. Biochem Biophys Res Commun 2007; 358: 117–23.
- 25 Seki T, Ihara I, Sugimura A et al . Isolation and expression of cDNA for different forms of hepatocyte growth factor from human leukocyte. Biochem Biophys Res Commun 1990; 172: 321–7.
- 26 Heidenreich R, Machein M, Nicolaus A et al . Inhibition of solid tumor growth by gene transfer of VEGF receptor-1 mutants. Int J Cancer 2004; 111: 348–57.
- 27 Chang YS, Adnane J, Trail PA et al . Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 2007; 59: 561–74.
- 28 Gasparini G, Longo R, Toi M, Ferrara N. Angiogenic inhibitors: a new therapeutic strategy in oncology. Nat Clin Pract Oncol 2005; 2: 562–77.
- 29 Saimura M, Nagai E, Mizumoto K et al . Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice. Cancer Gene Ther 2002; 9: 799–806.
- 30 Murakami M, Nagai E, Mizumoto K et al . Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice. Int J Cancer 2005; 117: 160–5.
- 31 Qiao H, Hung W, Tremblay E et al . Constitutive activation of met kinase in non-small-cell lung carcinoma correlates with anchorage-independent cell survival. J Cell Biochem 2002; 86: 665–77.
- 32 Abounader R, Lal B, Luddy C et al . In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis. FASEB J 2002; 16: 108–10.
- 33 Nemunaitis J, Cunningham C, Buchanan A et al . Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Ther 2001; 8: 746–59.
- 34 Reid T, Warren R, Kirn D. Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther 2002; 9: 979–86.
- 35 Wen J, Matsumoto K, Taniura N, Tomioka D, Nakamura T. Hepatic gene expression of NK4, an HGF-antagonist/angiogenesis inhibitor, suppresses liver metastasis and invasive growth of colon cancer in mice. Cancer Gene Ther 2004; 11: 419–30.
- 36 Kim KS, Kim HS, Park JS, Kwon YG, Park YS. Inhibition of B16BL6 tumor progression by coadministration of recombinant angiostatin K1-3 and endostatin genes with cationic liposomes. Cancer Gene Ther 2004; 11: 441–9.
