title: Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis.
abstract: The gene encoding the receptor for hyaluronan-mediated motility (RHAMM) is overexpressed in many human cancers. However, it is unclear whether RHAMM plays a causal role in tumor initiation or progression. Using somatic gene transfer in a mouse model of islet cell tumorigenesis, we demonstrate that RHAMM isoform B (RHAMM(B)) promotes tumor growth and metastases to lymph nodes and the liver. The propensity of RHAMM(B)-expressing cells to metastasize to the liver was confirmed using an experimental metastasis assay in which cells were injected into the tail vein of immunodeficient mice. However, RHAMM(B) did not increase cell migration or proliferation in culture. In initial efforts to identify signaling pathways activated by RHAMM(B), we found that RHAMM(B) induced phosphorylation of epidermal growth factor receptor (EGFR), Erk1/2, and STAT3 and conferred susceptibility to apoptosis after treatment with an EGFR inhibitor, gefitinib. Taken together, the results indicate that RHAMM(B) promotes hepatic metastasis by islet tumor cells, perhaps through growth factor receptor-mediated signaling.
authors.affiliation: Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. nad2012@med.cornell.edu
authors.forename: Yi-Chieh Nancy
authors.initials: YC
authors.lastname: Du
authors.forename: Chen-Kung
authors.initials: CK
authors.lastname: Chou
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
mesh_terms: D007516:Adenoma, Islet Cell / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D018014:Gene Transfer Techniques; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000556:secondary*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C098946:hyaluronan-mediated motility receptor; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3