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Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation.

ABSTRACT: Multiple myeloma (MM) is preceded by the asymptomatic pre-malignant state, monoclonal gammopathy of undetermined significance (MGUS). Although MGUS patients may remain stable for years, they are at increased risk of progressing to MM. A better understanding of the relevant molecular changes underlying the transition from an asymptomatic to symptomatic disease state is urgently needed. Our studies show for the first time that the CD147 molecule (extracellular matrix metalloproteinase inducer) may be having an important biological role in MM. We first demonstrate that CD147 is overexpressed in MM plasma cells (PCs) vs normal and pre-malignant PCs. Next, functional studies revealed that the natural CD147 ligand, cyclophilin B, stimulates MM cell growth. Moreover, when MM patient PCs displaying bimodal CD147 expression were separated into CD147(bright) and CD147(dim) populations and analyzed for proliferation potential, we discovered that CD147(bright) PCs displayed significantly higher levels of cell proliferation than did CD147(dim) PCs. Lastly, CD147-silencing significantly attenuated MM cell proliferation. Taken together, these data suggest that the CD147 molecule has a key role in MM cell proliferation and may serve as an attractive target for reducing the proliferative compartment of this disease.

SUBMITTER: Arendt BK

PROVIDER: S-EPMC3915875 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation.

Arendt B K BK Walters D K DK Wu X X Tschumper R C RC Huddleston P M PM Henderson K J KJ Dispenzieri A A Jelinek D F DF

Leukemia 20120330 10

Multiple myeloma (MM) is preceded by the asymptomatic pre-malignant state, monoclonal gammopathy of undetermined significance (MGUS). Although MGUS patients may remain stable for years, they are at increased risk of progressing to MM. A better understanding of the relevant molecular changes underlying the transition from an asymptomatic to symptomatic disease state is urgently needed. Our studies show for the first time that the CD147 molecule (extracellular matrix metalloproteinase inducer) may ...[more]

PMID: 22460757

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Project description:BackgroundThe BRAF inhibitor vemurafenib (PLX) has shown promise in treating metastatic melanoma, but most patients develop resistance to treatment after 6 mo. We identified a transmembrane protein, extracellular matrix metalloproteinase inducer (EMMPRIN) as a cell surface receptor highly expressed by PLX-resistant melanoma. Using an S100A9 ligand, we created an EMMPRIN targeted probe and liposome that binds to melanoma cells in vivo, thus designing a novel drug delivery vehicle.MethodsPLX-resistant cells were established through continuous treatment with PLX-4032 over the course of 1 y. Both PLX-resistant and sensitive melanoma cell lines were evaluated for the expression of unique cell surface proteins, which identified EMMPRIN as an overexpressed protein in PLX0-resistant cells and S100A9 is a ligand for EMMPRIN. To design a probe for EMMPRIN, S100A9 ligand was conjugated to a CF-750 near-infrared (NIR) dye. EMMPRIN targeted liposomes were created to encapsulate CF-750 NIR dye. Liposomes were characterized by scanning electron microscopy, flow cytometry, and in vivo analysis. A2058PLX and A2058 cells were subcutaneously injected into athymic mice. S100A9 liposomes were intravenously injected and tumor accumulation was evaluated using NIR fluorescent imaging.ResultsWestern blot and flow cytometry demonstrated that PLX sensitive and resistant A2058 and A375 melanoma cells highly express EMMPRIN. S100A9 liposomes were 200 nm diameter and uniformly sized. Flow cytometry demonstrated 100X more intracellular dye uptake by A2058 cells treated with S100A9 liposomes compared with untargeted liposomes. In vivo accumulation of S100A9 liposomes within subcutaneous A2058 and A2058PLX tumors was observed from 6-48 h, with A2058PLX accumulating significantly higher levels (P = 0.001626).ConclusionsEMMPRIN-targeted liposomes via an S100A9 ligand are a novel, targeted delivery system which could provide improved EMMPRIN specific drug delivery to a tumor.

Project description:BACKGROUND: Extracellular matrix metalloproteinase inducer (EMMPRIN) regulates several biological functions involving the modulation of cell behaviors via cell-cell and cell-matrix interactions. According to its diverse functions, we hypothesized that EMMPRIN may play an important role in endometrial remodeling and establishment of pregnancy in cow. METHODS: In this study, endometrial tissues from the cyclic cows during before ovulation, after ovulation and middle of estrous cycle; and pregnant endometrial tissues from Day 19 to 35 of gestation have been used. Expression of mRNA was analyzed by RT-PCR, qPCR and in situ hybridization whereas protein expression by immunohistochemistry and western blot analysis. RESULTS: EMMPRIN mRNA was expressed in both cyclic and pregnant endometrium and significantly higher in the endometrium at Day 35 of gestation than the cyclic endometrium. In Western blot analysis, an approximately 65 kDa band was detected in the endometrium, and approximately 51 kDa in the cultured bovine epithelial cells and BT-1 cells, respectively. Both in situ hybridization and immunohistochemistry data showed that EMMPRIN was primarily expressed in luminal and glandular epithelium with strong staining on Day 19 conceptus. At Day 19 of gestation, expression of EMMPRIN mRNA on luminal epithelium was decreased than that observed at middle of estrous cycle, however, on Day 30 of gestation, slightly increased expression was found at the site of placentation. Expression of matrix metalloproteinase-2 (MMP-2) and MMP-14 mRNA were mainly detected in stroma and their expression also decreased at Day 19 of gestation however it was also expressed at the site of placentation at Day 30 of gestation as observed for EMMPRIN. Expression of MMP-1 or -9 mRNA was very low and was below the detection limit in the cyclic and pregnant endometrium. CONCLUSION: EMMPRIN from the luminal epithelium may regulate the expression of stromal MMP-2 and -14 suggesting its crucial role in adhesion and fusion of embryo to luminal epithelium by directly itself through physiological tissues remodeling and developmental process, and/or stimulating MMPs to compensate endometrial functions.

Project description:Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen-rich bone matrix by activated osteoclasts results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP13 largely localizes to the stromal compartment compared with CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP13 expression in bone stromal cells. Because of its ability to degrade type I collagen, we examined whether bone stromal-derived MMP13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild-type or MMP13-null mice. In independent in vivo studies, MMP13-null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared with wild-type controls. Unexpectedly, no differences in type I collagen processing between the groups were observed. Ex vivo stromal coculture assays showed reduced formation and activity in MMP13-null osteoclasts. Analysis of soluble factors from wild-type and MMP13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly selective MMP13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. SIGNIFICANCE: Genetic and pharmacologic approaches show that bone stromal-derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2415/F1.large.jpg.

Dataset Information

Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation.

Publications

Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation.

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