Glioma inhibition by HGF/NK2, an antagonist of scatter factor/hepatocyte growth factor.
Strategies that antagonize growth factor signaling are attractive candidates for the biological therapy of brain tumors. HGF/NK2 is a secreted truncated splicing variant and potential antagonist of scatter factor/hepatocyte growth factor (SF/HGF), a multifunctional cytokine involved in the malignant progression of solid tumors including glioblastoma. U87 human malignant glioma cells that express an autocrine SF/HGF stimulatory loop were transfected with the human HGF/NK2 cDNA and clonal cell lines that secrete high levels of HGF/NK2 protein (U87-NK2) were isolated. The effects of HGF/NK2 gene transfer on the U87 malignant phenotype were examined. HGF/NK2 gene transfer had no effect on 2-dimensional anchorage-dependent cell growth. In contrast, U87-NK2 cell lines were approximately 20-fold less clonogenic in soft agar and approximately 4-fold less migratory than control-transfected cell lines. Intracranial tumor xenografts derived from U87-NK2 cells grew much slower than controls. U87-NK2 tumors were approximately 50-fold smaller than controls at 21 days post-implantation and HGF/NK2 gene transfer resulted in a trend toward diminished tumorigenicity. This report shows that the predominant effect of transgenic HGF/NK2 overexpression by glioma cells that are autocrine for SF/HGF stimulation is to inhibit their malignant phenotype.
Guerin
C
C
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Luddy
C
C
Abounader
R
R
Lal
B
B
Laterra
J
J
D000362:Agar / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D019898:Autocrine Communication; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002455:Cell Division; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018014:Gene Transfer Techniques; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008970:Molecular Weight; D009368:Neoplasm Transplantation / Q000473:pathology; D010641:Phenotype; D014162:Transfection; D014183:Transplantation, Heterologous / Q000473:pathology; D014407:Tumor Cells, Cultured
D017228:Hepatocyte Growth Factor; D000362:Agar