Tumor suppression effect using NK4, a molecule acting as an antagonist of HGF, on human gastric carcinomas

Abstract

Hepatocyte growth factor ( HGF ) is involved in malignant behavior of cancers as a mediator of tumor-stromal interactions, facilitating tumor invasion and metastasis. We have investigated whether a blockade of HGF using recombinant NK4, an HGF antagonist, would lead to growth inhibition of the human gastric carcinoma cell line, TMK1. To evaluate the function of endogenous NK4 and investigate its potential inhibitory effect, TMK1 cells were transfected with NK4 plasmid. After selection, NK4-expressing cells ( T11 ) were obtained, and cell growth was evaluated. Significant growth inhibition was observed in the T11-group compared to the control both in vitro and in vivo. Moreover, we investigated the effect of exogenous NK4 transferred by an adenovirus vector ( AdCMV.NK4 ). Cell proliferation of AdCMV.NK4 infected TMK1 cells was significantly inhibited compared with the control group. We also assessed the in vivo tumor suppression effect of AdCMV.NK4. The tumor volume following treatment with AdCMV.NK4 was significantly inhibited compared to that of the control group. These findings indicate that NK4 gene expression has a potential role in controlling proliferation of cancer cells. In conclusion, NK4 is a promising therapeutic agent and its gene delivery may be a new approach to treating patients with advanced gastric cancer.

Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy

“…39 So far, NK4 gene therapy has demonstrated efficacy in tumor models in which the involvement of the HGF-cMET signaling pathway in pathogenesis has been clearly established. [8][9][10][11][12][13][14][15][16][17][18][19][20] Based on the multifunctional properties of NK4 on various growth factors, 3,4,12,40 we propose that NK4 gene therapy would have therapeutic value for a wider range of tumors than only cMET overexpressing carcinomas. However, application of NK4 gene therapy to specific tumor types such as HCC for which the effect of the HGF-cMET signaling is less explicit or may even be inhibitory on carcinogenesis [32][33][34] needed further assessment.…”

“…[3][4][5][6] NK4, which consists of the N-terminal hairpin domain and the four subsequent kringle domains of HGF, competitively inhibits the multiple biological activities of HGF through binding to cMET and is suggested to have a broad antiangiogenic activity through its kringle domain structure. 3,4,7 Previous in vivo studies confirmed therapeutic efficacy of NK4 gene therapy for glioblastoma, prostate, breast, gastric, pancreatic, gall bladder and colon cancers [8][9][10][11][12][13][14][15][16][17][18][19][20] and recommended further preclinical evaluation of NK4 gene therapy as anticancer agent. However, NK4 gene therapy for treatment of HCC could be argued against because the antitumor effects of NK4 in part rely on its antagonistic activity to HGF 3 and the role of the HGF-cMET system in hepatocarcinogenesis has not been clearly established.…”

Endocrine Delivery System of NK4, an HGF-Antagonist and Anti-Angiogenic Regulator, for Inhibitions of Tumor Growth, Invasion and Metastasis

“…Thus, NK4 may also have utility for anti-tumor immunotherapy. There is now ample evidence that NK4 is useful for the inhibition of growth, invasion and metastasis in various types of tumors, such as gastric carcinoma (Hirao et al, 2002), pancreas cancer (Tomioka et al, 2001), prostate cancer (Davies et al, 2003), multiple myeloma (Du et al, 2007) and melanoma (Kishi et al, 2009) (Table-1). These results support our hypothesis that HGF is a key determinant of tumor malignancy (Matsumoto et al, 1996b Adeno-NK4, adenoviral vector carrying NK4 cDNA; r-NK4, recombinant NK4 protein; sc, subcutaneous; iv, intravenous; ip, intraperitoneal; im, intramuscular; DC, dendritic cells; and CTL, cytotoxic T lymphocytes.…”

Gene Therapy Strategies for Hepatocellular Carcinoma

“…The antitumor effect was related to a decrease in density of microvessels in tumors. NK4, a hepatocyte growth factor (HGF) antagonist, is another antiangiogenic factor that has been demonstrated to exhibit antitumor activity in many tumors, too [92][93][94][95]. NK4 consists of the Nterminal hairpin domain and the four subsequent kringle domain of HGF.…”