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Reduced HGF expression in subcutaneous CT26 tumor genetically modified to secrete NK4 and its possible relation with antitumor effects.
- Source :
-
Cancer science [Cancer Sci] 2004 Apr; Vol. 95 (4), pp. 321-7. - Publication Year :
- 2004
-
Abstract
- Tumor-stromal interactions, which are regulated by stromal-derived HGF and tumor-derived HGF inducers, are essential for tumor cell acquisition of such malignant properties as invasion and metastasis. NK4, a proteolytic cleavage product of HGF, has antitumor activities as both an HGF antagonist and an angiogenesis inhibitor. In this study, we examined the in vitro and in vivo behaviors of mouse colon adenocarcinoma C T26 cells modified by gene transfer to secrete NK4, and investigated the influence of NK4 on expression of HGF and HGF inducers associated with tumor-stromal interactions. In vitro cell proliferation rates of NK4 transfectant (C T26-NK4) and mock transfectant (C T26-NEO) were essentially the same, and scattering and invasion were stimulated by HGF in C T26-NEO, but not in C T26-NK4. In syngeneic BALB/c female mice, subcutaneous tumor growth of C T26-NK4 was potently suppressed, and the survival was prolonged significantly. Immunohistochemistry showed significantly decreased microvessels and increased apoptotic cells in C T26-NK4 tumor compared with control. Interestingly, HGF, strongly expressed in C T26-NEO tumor stroma, was reduced in C T26-NK4. In vitro, conditioned medium of C T26-NK4 inhibited fibroblast-derived HGF production, which was increased by that of C T26-NEO. Moreover, although similar constitutive expression levels of PDGF and TGF-alpha (both HGF inducers) were detected in C T26-NK4 and C T26-NEO in semiquantitative RT-PCR analyses, the expression was up-regulated by HGF in C T26-NEO, but not C T26-NK4. These results suggest that NK4 may exert antitumor activities not only by antagonizing HGF, but also by inhibiting HGF amplification via tumor-stromal interactions. Continuous, abundant NK4 production induced at a tumor site by gene transfer should show multiple antitumor activities with potential therapeutic benefit.
- Subjects :
- Adenocarcinoma pathology
Animals
Cell Division
Cell Line, Tumor metabolism
Colonic Neoplasms pathology
Female
Fibroblasts metabolism
Hepatocyte Growth Factor antagonists & inhibitors
Hepatocyte Growth Factor genetics
Hepatocyte Growth Factor pharmacology
Humans
Mice
Mice, Inbred BALB C
Neoplasm Transplantation
Phenotype
Platelet-Derived Growth Factor metabolism
Recombinant Proteins antagonists & inhibitors
Recombinant Proteins pharmacology
Stromal Cells metabolism
Transfection
Transforming Growth Factor alpha metabolism
Adenocarcinoma metabolism
Colonic Neoplasms metabolism
Gene Expression Regulation, Neoplastic
Hepatocyte Growth Factor biosynthesis
Hepatocyte Growth Factor metabolism
Mitogens
Subjects
Details
- Language :
- English
- ISSN :
- 1347-9032
- Volume :
- 95
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 15072590
- Full Text :
- https://doi.org/10.1111/j.1349-7006.2004.tb03210.x