Anti-Human CD138 monoclonal antibody

In this study, we assessed the changes and prognostic relevance of syndecan-1 (SDC1) tissue and serum levels in bladder cancer (BC). SDC1 levels were analyzed in 213 samples (119 paraffin-embedded and 79 serum samples of BC patients and 15 controls) using immunohistochemistry and enzyme-linked immunosorbent assay. Results were correlated with clinicopathological characteristics and follow-up data, as well as previously determined serum levels of angiogenic factors (basic fibroblast growth factor, endostatin, angiostatin, angiopoietin, vascular endothelial growth factor, Tie2 and MMP-7). SDC1 staining was present in the cell membrane of normal bladder epithelium and non muscle-invasive BC cells but was absent in a significant proportion of muscle-invasive carcinomas (P < .001). In contrast, stromal SDC1 expression was enhanced in muscle-invasive compared to non muscle-invasive BCs (P = .001). Serum concentrations of the SDC1 ectodomain were higher in muscle-invasive BCs compared to controls or non muscle-invasive carcinomas (P < .001 each). Lymph node positive cases had the highest SDC1 serum concentrations (P < .001). SDC1 expression in stromal cells was independently associated with survival (hazard ratio = 2.034, 95% confidence interval 1.176-3.519, P = .011). SDC1 serum concentrations correlated with those of endostatin and matrix metalloproteinase 7. Loss of SDC1 in tumor cells and the parallel increase of serum SDC1 ectodomain concentration in high-stage, high-grade BCs suggest the involvement of SDC1 shedding in BC progression. In addition, high preoperative SDC1 serum levels may help to identify patients with lymph node metastases, supporting therapeutic decision-making. Presence of SDC1 in tumor stroma is an independent risk factor for patient survival and may therefore be used to select patients for more aggressive therapy. (C) 2014 Elsevier Inc. All rights reserved.

Mounting evidence implicates stromal fibroblasts in breast carcinoma progression. We have recently shown in three-dimensional coculture experiments that human mammary fibroblasts stimulate the proliferation of T47D breast carcinoma cells and that this activity requires the shedding of the heparan sulfate proteoglycan syndecan-1 (Sdc1) from the fibroblast surface. The goal of this project was to determine the mechanism of Sdc1 ectodomain shedding. The broad spectrum matrix metalloproteinase (MMP) inhibitor GM6001 specifically blocked Sdc1-mediated carcinoma cell growth stimulation, pointing toward MMPs as critical enzymes involved in Sdc1 shedding. MMP-2 and membrane type I MMP (MT1-MMP) were the predominant MMPs expressed by the mammary fibroblasts. Fibroblast-dependent carcinoma cell growth stimulation in three-dimensional coculture was abolished by MT1-MMP expression silencing with small interfering RNA and restored either by adding recombinant MT1-MMP catalytic domain or by expressing a secreted form of Sdc1 in the fibroblasts. These findings are consistent with a model where fibroblast-derived MT1-MMP cleaves Sdc1 at the fibroblast surface, leading to paracrine growth stimulation of carcinoma cells by Sdc1 ectodomain. The relevance of MT1-MMP in paracrine interactions was further supported by coculture experiments with T47D cells and primary fibroblasts isolated from human breast carcinomas or matched normal breast tissue. Carcinoma-associated fibroblasts stimulated T47D cell proliferation significantly more than normal fibroblasts in three-dimensional coculture. Function-blocking anti-MT1-MMP antibody significantly inhibited the T47D cell growth stimulation in coculture with primary fibroblasts. In summary, these results ascribe a novel role to fibroblast-derived MT1-MMP in stromal-epithelial signaling in breast carcinomas. [Cancer Res 2008;68(22):9558-65]