title: ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer.
abstract: ADAM15 is a member of a family of catalytically active disintegrin membrane metalloproteinases that function as molecular signaling switches, shed membrane bound growth factors and/or cleave and inactivate cell adhesion molecules. Aberrant metalloproteinase function of ADAM15 may contribute to tumor progression through the release of growth factors or disruption of cell adhesion. In this study, we utilized human bladder cancer tissues and cell lines to evaluate the expression and function of ADAM15 in the progression of human bladder cancer. Examination of genome and transcriptome databases revealed that ADAM15 ranked in the top 5% of amplified genes and its mRNA was significantly overexpressed in invasive and metastatic bladder cancer compared to noninvasive disease. Immunostaining of a bladder tumor tissue array designed to evaluate disease progression revealed increased ADAM15 immunoreactivity associated with increasing cancer stage and exhibited significantly stronger staining in metastatic samples. About half of the invasive tumors and the majority of the metastatic cases exhibited high ADAM15 staining index, while all low grade and noninvasive cases exhibited negative or low staining. The knockdown of ADAM15 mRNA expression significantly inhibited bladder tumor cell migration and reduced the invasive capacity of bladder tumor cells through MatrigelTM and monolayers of vascular endothelium. The knockdown of ADAM15 in a human xenograft model of bladder cancer inhibited tumor growth by 45% compared to controls. Structural modeling of the catalytic domain led to the design of a novel ADAM15-specific sulfonamide inhibitor that demonstrated bioactivity and significantly reduced the viability of bladder cancer cells in vitro and in human bladder cancer xenografts. Taken together, the results revealed an undescribed role of ADAM15 in the invasion of human bladder cancer and suggested that the ADAM15 catalytic domain may represent a viable therapeutic target in patients with advanced disease.
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Lorenzatti Hiles
authors.affiliation: Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Bucheit
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Rubin
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.|School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hayward
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Angelica L
authors.initials: AL
authors.lastname: Cates
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Day
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.|European Egyptian Pharmaceuticals, Alexandria, Egypt.
authors.forename: Layla
authors.initials: L
authors.lastname: El-Sawy
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: L Priya
authors.initials: LP
authors.lastname: Kunju
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daignault
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Cheryl T
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Liebert
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Day
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D030541:Databases, Genetic; D018450:Disease Progression; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009367:Neoplasm Staging; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D051722:ADAM Proteins; C098660:ADAM15 protein, human