title: Enhanced growth of human met-expressing xenografts in a new strain of immunocompromised mice transgenic for human hepatocyte growth factor/scatter factor.
abstract: 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.
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Zhang
authors.forename: Yanli
authors.initials: Y
authors.lastname: Su
authors.forename: Nathan
authors.initials: N
authors.lastname: Lanning
authors.forename: Margaret
authors.initials: M
authors.lastname: Gustafson
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Brian
authors.initials: B
authors.lastname: Cao
authors.forename: Galia
authors.initials: G
authors.lastname: Tsarfaty
authors.forename: Ling-Mei
authors.initials: LM
authors.lastname: Wang
authors.forename: Rick
authors.initials: R
authors.lastname: Hay
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
mesh_terms: 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
chemical_list: D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met