Receptor Activator of NF-κB Ligand Enhances Breast Cancer–Induced Osteolytic Lesions through Upregulation of Extracellular Matrix Metalloproteinase Inducer/CD147

Abstract

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-κB 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. Cancer Res; 70(15); 6150-60.

Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

“…Endo180 and CD147 have both been correlated with low levels of E-cadherin in tumor tissue, and both are under the transcriptional regulation of the core EMT trigger TGFb (7,8,19,20). In an aligned study, we have demonstrated that the stiff microenvironment associated with advanced glycation endproduct accumulation and collagen crosslinking of the basement membrane in the prostate gland is sufficient to activate an EMTlike phenotype in PEC acini by forcing the relocalization of Endo180 into endosomes and initiating an Endo180-dependent contractile signaling cascade that promotes cell invasion (21).…”

Regulation of invadopodia formation and activity by CD147

“…Mechanisms of regulation of endogenous CD147 expression are not well established, although several growth factors and cytokines have been shown to increase CD147 levels in a variety of contexts (Hagemann et al, 2005;Menashi et al, 2003;Reddy et al, 2010;Rucci et al, 2010). Previous studies have shown that Src is a crucial regulator of invadopodia formation (Murphy and Courtneidge, 2011), and a recent study showed that the Src family kinase, Fyn kinase, induces emmprin expression (Ramos and Dang, 2011).…”

Molecular Pathways: Osteoclast-Dependent and Osteoclast-Independent Roles of the RANKL/RANK/OPG Pathway in Tumorigenesis and Metastasis

“…Expression analyses and treatment of cells in vitro with RANKL have shown functional RANK protein expression on the surface of prostate, breast, osteosarcoma, melanoma, and lung cancer cell lines. In most studies, RANKL does not seem to increase proliferation of RANK-expressing tumor cells (46,47), although increased cell number and protection against DNA damage-induced cell death, activated by either chemotherapy or g-irradiation, have been observed in certain cell lines (43). In addition, RANKL will affect a variety of other tumor cell behaviors potentially relevant to tumor progression and metastasis, including increased tumor cell growth in semisolid media, loss of apical-basal polarity, and stimulated migration and invasion (38,43,45,46,48,49).…”

“…In addition, RANKL will affect a variety of other tumor cell behaviors potentially relevant to tumor progression and metastasis, including increased tumor cell growth in semisolid media, loss of apical-basal polarity, and stimulated migration and invasion (38,43,45,46,48,49). RANKL treatment has been documented to induce a variety of factors potentially involved in migration, angiogenesis, and invasion, including MMP1, MMP9, the matrix metalloproteinase inducer EMMPRIN/CD47, ICAM-1, IL-6, IL-8, and VEGF (47), and it can decrease expression of the metastasis suppressor serpin 5b/maspin (50).…”