Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4

Daniëlle A M Heideman, Victor W. van Beusechem, Elisabeth Bloemena, Peter J F Snijders, Mikael E. Craanen, G. Johan A Offerhaus, Patrick W B Derksen, Michiel de Bruin, M. Adhiambo Witlox, Bonnie Molenaar, Chris J L M Meijer, Winald R. Gerritsen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)317-327
Number of pages11
JournalJournal of Gene Medicine
Volume6
Issue number3
DOIs
StatePublished - Mar 2004
Externally publishedYes

Fingerprint

Adenoviridae
Stomach Neoplasms
Growth
Neoplasms
Stomach
Neoplasm Metastasis
Angiogenesis Inhibitors
Therapeutics
Stromal Cells
Microvessels
Heterografts
Genetic Therapy
Endothelial Cells
Epithelial Cells
Immunohistochemistry
Carcinoma
Proteins

Keywords

  • c-MET
  • Gene therapy
  • Hepatocyte growth factor
  • Mitogen
  • Motogen

ASJC Scopus subject areas

  • Genetics

Cite this

Heideman, D. A. M., van Beusechem, V. W., Bloemena, E., Snijders, P. J. F., Craanen, M. E., Offerhaus, G. J. A., ... Gerritsen, W. R. (2004). Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4. Journal of Gene Medicine, 6(3), 317-327. https://doi.org/10.1002/jgm.523

Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4. / Heideman, Daniëlle A M; van Beusechem, Victor W.; Bloemena, Elisabeth; Snijders, Peter J F; Craanen, Mikael E.; Offerhaus, G. Johan A; Derksen, Patrick W B; de Bruin, Michiel; Witlox, M. Adhiambo; Molenaar, Bonnie; Meijer, Chris J L M; Gerritsen, Winald R.

In: Journal of Gene Medicine, Vol. 6, No. 3, 03.2004, p. 317-327.

Research output: Contribution to journalArticle

Heideman, DAM, van Beusechem, VW, Bloemena, E, Snijders, PJF, Craanen, ME, Offerhaus, GJA, Derksen, PWB, de Bruin, M, Witlox, MA, Molenaar, B, Meijer, CJLM & Gerritsen, WR 2004, 'Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4', Journal of Gene Medicine, vol. 6, no. 3, pp. 317-327. https://doi.org/10.1002/jgm.523
Heideman DAM, van Beusechem VW, Bloemena E, Snijders PJF, Craanen ME, Offerhaus GJA et al. Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4. Journal of Gene Medicine. 2004 Mar;6(3):317-327. https://doi.org/10.1002/jgm.523
Heideman, Daniëlle A M ; van Beusechem, Victor W. ; Bloemena, Elisabeth ; Snijders, Peter J F ; Craanen, Mikael E. ; Offerhaus, G. Johan A ; Derksen, Patrick W B ; de Bruin, Michiel ; Witlox, M. Adhiambo ; Molenaar, Bonnie ; Meijer, Chris J L M ; Gerritsen, Winald R. / Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4. In: Journal of Gene Medicine. 2004 ; Vol. 6, No. 3. pp. 317-327.
@article{5b1dca4647c244de841ec7154c63da9a,
title = "Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4",
abstract = "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.",
keywords = "c-MET, Gene therapy, Hepatocyte growth factor, Mitogen, Motogen",
author = "Heideman, {Dani{\"e}lle A M} and {van Beusechem}, {Victor W.} and Elisabeth Bloemena and Snijders, {Peter J F} and Craanen, {Mikael E.} and Offerhaus, {G. Johan A} and Derksen, {Patrick W B} and {de Bruin}, Michiel and Witlox, {M. Adhiambo} and Bonnie Molenaar and Meijer, {Chris J L M} and Gerritsen, {Winald R.}",
year = "2004",
month = "3",
doi = "10.1002/jgm.523",
language = "English (US)",
volume = "6",
pages = "317--327",
journal = "Journal of Gene Medicine",
issn = "1099-498X",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4

AU - Heideman, Daniëlle A M

AU - van Beusechem, Victor W.

AU - Bloemena, Elisabeth

AU - Snijders, Peter J F

AU - Craanen, Mikael E.

AU - Offerhaus, G. Johan A

AU - Derksen, Patrick W B

AU - de Bruin, Michiel

AU - Witlox, M. Adhiambo

AU - Molenaar, Bonnie

AU - Meijer, Chris J L M

AU - Gerritsen, Winald R.

PY - 2004/3

Y1 - 2004/3

N2 - 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.

AB - 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.

KW - c-MET

KW - Gene therapy

KW - Hepatocyte growth factor

KW - Mitogen

KW - Motogen

UR - http://www.scopus.com/inward/record.url?scp=7444226277&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=7444226277&partnerID=8YFLogxK

U2 - 10.1002/jgm.523

DO - 10.1002/jgm.523

M3 - Article

VL - 6

SP - 317

EP - 327

JO - Journal of Gene Medicine

JF - Journal of Gene Medicine

SN - 1099-498X

IS - 3

ER -