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

Abstract

Multiple myeloma (MM) 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 MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166− cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells. CD166 deficiency in MM cell lines or CD138+ BM cells from MM patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Further, CD166 deficiency in MM cells also reduced formation of osteolytic disease in vivo after intra-tibial engraftment. Mechanistic investigation revealed that CD166 expression in MM cells inhibited osteoblastogenesis of BM-derived osteoblast progenitors by suppressing RUNX2 gene expression. Conversely, CD166 expression in MM cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in MM cell homing to the BM and MM progression, rationalizing its further study as a candidate therapeutic target for MM treatment.

Endophilin-A3 and Galectin-8 control the clathrin-independent endocytosis of CD166

“…Importantly, CD166 is overexpressed in various types of tumors where its expression level/cell surface abundance correlates with poor prognosis [11][12][13][14][15][16] . More recently, CD166 has been identified as a cancer stem cell marker 12,17 , and proposed as a target for immunotherapy [18][19][20][21][22] . Despite its apparent importance in cancer progression, the trafficking mechanisms regulating the homeostasis of CD166 at the cell surface remain unknown.…”

Plasmacytoma in patients with multiple myeloma: morphology and immunohistochemistry

“…In addition, CD166 activated osteoclastogenesis, shifting the balance between RANKL and osteoprotegerin. CD166 blockade in mouse myeloma cells resulted in longer survival, a lower total tumour mass, and less pronounced osteolysis than in mouse with CD166-positive cells [20]. Thus, it is assumed that CD166 is a predictor for lytic bone lesions, as it participates in osteogenic modulation.…”

Plasmacytoma in patients with multiple myeloma: morphology and immunohistochemistry

“…CD166 blockade in mouse myeloma cells resulted in longer survival, a lower total tumour mass, and less pronounced osteolysis than in mouse with CD166-positive cells. 20 Thus, it is assumed that CD166 is a predictor for lytic bone lesions, as it participates in osteogenic modulation.…”