Enhanced growth of human met-expressing xenografts in a new strain of immunocompromised mice transgenic for human hepatocyte growth factor/scatter factor.
Downstream signaling that results from the interaction of hepatocyte growth factor/scatter factor (HGF/SF) with the receptor tyrosine kinase Met plays critical roles in tumor development, progression, and metastasis. This ligand-receptor pair is an attractive target for new diagnostic and therapeutic agents, preclinical development of which requires suitable animal models. The growth of heterotopic and orthotopic Met-expressing human tumor xenografts in conventional strains of immunocompromised mice inadequately replicates the paracrine stimulation by human HGF/SF (hHGF/SF) that occurs in humans with cancer. We have therefore generated a mouse strain transgenic for hHGF/SF (designated hHGF-Tg) on a severe combined immunodeficiency (SCID) background. We report here that the presence of ectopically expressed hHGF/SF ligand significantly enhances growth of heterotopic subcutaneous xenografts derived from human Met-expressing cancer cells, including the lines SK-LMS-1 (human leiomyosarcoma), U118 (human glioblastoma), and DU145 (human prostate carcinoma), but not that of M14-Mel xenografts (human melanoma that expresses insignificant levels of Met). Our results indicate that ectopic hHGF/SF can specifically activate Met in human tumor xenografts. This new hHGF-Tg strain of mice should provide a powerful tool for evaluating drugs and diagnostic agents that target the various pathways influenced by Met activity.
Zhang
Yu-Wen
YW
Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.
Su
Yanli
Y
Lanning
Nathan
N
Gustafson
Margaret
M
Shinomiya
Nariyoshi
N
Zhao
Ping
P
Cao
Brian
B
Tsarfaty
Galia
G
Wang
Ling-Mei
LM
Hay
Rick
R
Vande Woude
George F
GF
D000818:Animals; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met