Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models.
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.
Kishi
Yuko
Y
Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Kuba
Keiji
K
Nakamura
Takahiro
T
Wen
Jinhua
J
Suzuki
Yoshinori
Y
Mizuno
Shinya
S
Nukiwa
Toshihiro
T
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000628:therapy*; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
C066855:HGF protein, human; D017228:Hepatocyte Growth Factor