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
Department of Gastroenterology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
J Gene Med. 2004 Mar;6(3):317-27. doi: 10.1002/jgm.523.
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.
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.
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.
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.
为改善胃癌患者的预后，开发针对肿瘤细胞恶性行为的新型治疗方式至关重要。就此而言，作为肝细胞生长因子（HGF）拮抗剂和血管生成抑制剂的NK4，可能是一种潜在的胃癌治疗药物。HGF-c-MET通路在胃癌的生长、侵袭、转移和血管生成中起关键作用。因此，本研究探讨腺病毒载体介导的NK4基因治疗对胃癌是否具有治疗潜力。
通过免疫组织化学研究正常和（癌前）恶性胃组织中HGF和c-MET的表达。在体外和体内研究腺病毒载体介导的NK4表达对胃癌细胞生物学行为的影响。
大多数胃癌（即76%）表达c-MET，并且在所有癌组织中，HGF在肿瘤细胞或基质细胞中表达。正常胃上皮细胞不表达这两种蛋白。用复制缺陷型腺病毒载体AdCMV.NK4转导胃癌细胞可有效产生和分泌NK4。因此，胃癌细胞的增殖、迁移和侵袭受到显著抑制。此外，血管内皮细胞的增殖显著降低，血管生成得到有效抑制。最后，用AdCMV.NK4治疗已建立的人胃肿瘤异种移植瘤，导致肿瘤生长明显延迟，肿瘤内微血管密度显著降低。
本研究表明，腺病毒载体介导的NK4表达是一种有前景的治疗人类胃癌的策略，可同时干扰原发性肿瘤的生长、转移和血管生成。
