» Articles » PMID: 19272140

Anti-metastatic Effects of Viral and Non-viral Mediated Nk4 Delivery to Tumours

Overview
Publisher Biomed Central
Date 2009 Mar 11
PMID 19272140
Citations 7
Authors
Affiliations
Soon will be listed here.
Abstract

The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metastasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate reduction in primary subcutaneous tumour growth. Overall, this study demonstrates the potential for Nk4 gene therapy of metastatic tumours, when delivered by AAV or non-viral methods.

Citing Articles

Adeno-associated virus (AAV) vectors in cancer gene therapy.

Santiago-Ortiz J, Schaffer D J Control Release. 2016; 240:287-301.

PMID: 26796040 PMC: 4940329. DOI: 10.1016/j.jconrel.2016.01.001.


Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts.

Zhu Y, Cheng M, Yang Z, Zeng C, Chen J, Xie Y Drug Des Devel Ther. 2014; 8:2449-62.

PMID: 25525335 PMC: 4267519. DOI: 10.2147/DDDT.S71466.


Adeno-associated virus-mediated cancer gene therapy: current status.

Luo J, Luo Y, Sun J, Zhou Y, Zhang Y, Yang X Cancer Lett. 2014; 356(2 Pt B):347-56.

PMID: 25444906 PMC: 4259838. DOI: 10.1016/j.canlet.2014.10.045.


Bacteria as vectors for gene therapy of cancer.

Baban C, Cronin M, OHanlon D, OSullivan G, Tangney M Bioeng Bugs. 2011; 1(6):385-94.

PMID: 21468205 PMC: 3056088. DOI: 10.4161/bbug.1.6.13146.


AAV2-mediated in vivo immune gene therapy of solid tumours.

Collins S, Buhles A, Scallan M, Harrison P, OHanlon D, OSullivan G Genet Vaccines Ther. 2010; 8:8.

PMID: 21172020 PMC: 3016353. DOI: 10.1186/1479-0556-8-8.


References
1.
Woude G, Jeffers M, Cortner J, Alvord G, Tsarfaty I, Resau J . Met-HGF/SF: tumorigenesis, invasion and metastasis. Ciba Found Symp. 1997; 212:119-30; discussion 130-2, 148-54. DOI: 10.1002/9780470515457.ch8. View

2.
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. 2001; 279(3):846-52. DOI: 10.1006/bbrc.2000.4034. View

3.
Xin L, Xu R, Zhang Q, LI T, Gan R . Kringle 1 of human hepatocyte growth factor inhibits bovine aortic endothelial cell proliferation stimulated by basic fibroblast growth factor and causes cell apoptosis. Biochem Biophys Res Commun. 2000; 277(1):186-90. DOI: 10.1006/bbrc.2000.3658. View

4.
Jo J, Yamamoto M, Matsumoto K, Nakamura T, Tabata Y . Liver targeting of plasmid DNA with a cationized pullulan for tumor suppression. J Nanosci Nanotechnol. 2006; 6(9-10):2853-9. DOI: 10.1166/jnn.2006.466. View

5.
Andino L, Conlon T, Porvasnik S, Boye S, Hauswirth W, Lewin A . Rapid, widespread transduction of the murine myocardium using self-complementary Adeno-associated virus. Genet Vaccines Ther. 2007; 5:13. PMC: 2222599. DOI: 10.1186/1479-0556-5-13. View