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Cancer Res. 2016 Dec 1;76(23):6901-6910. Epub 2016 Sep 7.

Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma.

Author information

1
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
2
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
3
Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
4
Eli Lilly, Indianapolis, Indiana.
5
Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, Dusseldorf, Germany.
6
Department of Pediatrics III, University Children's Hospital Essen, University Duisburg-Essen, Essen, Germany.
7
Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.
8
Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, Indiana.
9
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana. esrour@iu.edu.
10
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.

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.

PMID:
27634757
PMCID:
PMC5135585
DOI:
10.1158/0008-5472.CAN-16-0517
[Indexed for MEDLINE]
Free PMC Article

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