Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4.
BACKGROUND
To improve the prognosis of patients with gastric cancer it is important to develop novel treatment modalities targeting the malignant behavior of tumor cells. Concerning this, NK4, which acts as HGF-antagonist and angiogenesis inhibitor, might be a potential therapeutic agent for gastric cancer. The HGF-c-MET pathway plays a pivotal role in gastric tumor growth, invasion, metastasis and angiogenesis. Therefore, the current study investigates whether adenoviral vector-mediated NK4 gene therapy has therapeutic potential for gastric cancer.


METHODS
Expression of HGF and c-MET in normal and (pre-)malignant gastric tissue was studied by immunohistochemistry. The effects of adenoviral vector-mediated expression of NK4 on the biological behavior of gastric cancer cells were studied in vitro and in vivo.


RESULTS
The majority of gastric cancers, i.e. 76%, express c-MET and in all carcinomas HGF is expressed in either tumor or stromal cells. Normal gastric epithelial cells do not express either of these proteins. Transduction of gastric cancer cells with the replication-deficient adenoviral vector AdCMV.NK4 resulted in efficient production and secretion of NK4. Consequently, proliferation, migration and invasion of gastric cancer cells were significantly inhibited. In addition, significantly reduced proliferation of vascular endothelial cells and efficient inhibition of angiogenesis were achieved. Finally, treatment of established human gastric tumor xenografts with AdCMV.NK4 resulted in significant tumor growth delay and significant reduction of intratumoral microvessel density.


CONCLUSIONS
The present study shows that adenoviral vector-mediated expression of NK4 is a promising strategy to treat human gastric cancer by simultaneous interfering with primary tumor growth, metastasis and angiogenesis.
Heideman
Daniëlle A M
DA
Department of Gastroenterology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. dam.heideman@vumc.nl
van Beusechem
Victor W
VW
Bloemena
Elisabeth
E
Snijders
Peter J F
PJ
Craanen
Mikael E
ME
Offerhaus
G Johan A
GJ
Derksen
Patrick W B
PW
de Bruin
Michiel
M
Witlox
M Adhiambo
MA
Molenaar
Bonnie
B
Meijer
Chris J L M
CJ
Gerritsen
Winald R
WR
D000230:Adenocarcinoma / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002465:Cell Movement; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D007120:Immunochemistry; D051379:Mice; D008819:Mice, Nude; D008934:Mitogens / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000628:therapy*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018874:Spheroids, Cellular; D013274:Stomach Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C066855:HGF protein, human; D008934:Mitogens; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met