Receptor activator of NF-kappaB ligand enhances breast cancer-induced osteolytic lesions through upregulation of extracellular matrix metalloproteinase inducer/CD147.
Breast cancer shows a strong predilection to metastasize to bone. Cell surface glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN)/CD147 induces metalloproteinases (MMP) and vascular endothelial growth factor (VEGF), which may support osteoclastic activity and increased incidence of breast cancer bone metastases. In support of this hypothesis, we observed that MDA-MB-231 human breast tumor cells engineered to overexpress EMMPRIN strongly induced osteolytic lesions in immunodeficient mice, which was blunted by in vivo treatment with an EMMPRIN blocking antibody. Similarly, these cells exhibited increased expression of MMP-9 and VEGF relative to control cells. Treatment of MDA-MB-231 cells with the osteoclastogenic cytokine receptor activator of NF-kappaB ligand (RANKL) upregulated EMMPRIN expression with a parallel increase of MMP-9 and VEGF. Conditioned medium from osteoblasts similarly increased EMMPRIN, MMP-9, and VEGF expression in cells. Osteoblast treatment with the RANKL decoy receptor osteoprotegerin abolished this effect. EMMPRIN overexpression stimulated MDA-MB-231 cell invasion but not proliferation. Conversely, small interfering RNA-mediated knockdown of EMMPRIN downregulated MMP-9 and VEGF basal expression and RANKL-stimulated expression, and reduced cell invasion. Our results argue that EMMPRIN drives breast cancer-induced osteolytic lesions and that activation of the RANKL pathway increases EMMPRIN in osteotropic tumor cells, in turn enhancing tumor-induced bone resorption.
Rucci
Nadia
N
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Millimaggi
Danilo
D
Mari
Marianna
M
Del Fattore
Andrea
A
Bologna
Mauro
M
Teti
Anna
A
Angelucci
Adriano
A
Dolo
Vincenza
V
D000818:Animals; D051926:Basigin / Q000096:biosynthesis* / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053245:RANK Ligand / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
C497886:BSG protein, human; D053245:RANK Ligand; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C505688:TNFSF11 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051926:Basigin; D020780:Matrix Metalloproteinase 9