title: Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma.
abstract: Multiple myeloma is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here, we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in multiple myeloma cell lines and primary bone marrow cells from patients. CD166+multiple myeloma cells homed more efficiently than CD166-cells to the bone marrow of engrafted immunodeficient NSG mice. CD166 silencing in multiple myeloma cells enabled longer survival, a smaller tumor burden, and less osteolytic lesions, as compared with mice bearing control cells. CD166 deficiency in multiple myeloma cell lines or CD138+bone marrow cells from multiple myeloma patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Furthermore, CD166 deficiency in multiple myeloma cells also reduced the formation of osteolytic disease in vivo after intratibial engraftment. Mechanistic investigation revealed that CD166 expression in multiple myeloma cells inhibited osteoblastogenesis of bone marrow-derived osteoblast progenitors by suppressing Runx2 gene expression. Conversely, CD166 expression in multiple myeloma cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in multiple myeloma cell homing to the bone marrow and multiple myeloma progression, rationalizing its further study as a candidate therapeutic target for multiple myeloma treatment. Cancer Res; 76(23); 6901-10. ©2016 AACR.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Linlin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Colin
authors.initials: C
authors.lastname: Crean
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Bradley
authors.initials: B
authors.lastname: Poteat
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
authors.affiliation: Eli Lilly, Indianapolis, Indiana.
authors.forename: Christophe
authors.initials: C
authors.lastname: Machal
authors.affiliation: Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, Dusseldorf, Germany.|Department of Pediatrics III, University Children's Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Rafat
authors.initials: R
authors.lastname: Abonour
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.|Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Kacena
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.|Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, Indiana.
authors.forename: John
authors.initials: J
authors.lastname: Chirgwin
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.|Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, Indiana.
authors.forename: Attaya
authors.initials: A
authors.lastname: Suvannasankha
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana. esrour@iu.edu.|Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000009:adverse effects*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000009:adverse effects*; D002454:Cell Differentiation; D018450:Disease Progression; D005326:Fetal Proteins / Q000009:adverse effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000150:complications / Q000235:genetics* / Q000473:pathology; D010014:Osteolysis / Q000209:etiology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule