Extracellular Matrix Metalloprotease Inducer Stimulates Fibroblast‐Mediated Tumor Growth In Vivo

Rosenthal, Eben L.; Vidrine, D. Macy; Zhang, Wenyue

doi:10.1097/01.mlg.0000224368.58870.3c

Cited by 12 publications

(13 citation statements)

References 34 publications

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“…In this latter study, co-cultures of SKG-II cells and fibroblasts exhibited increased in vitro invasive activity of SKG-II cells via increased activation of fibroblast-derived proMMP-2 on the tumor cell surface. Promotion of tumorigenesis by co-injection of emmprin-expressing tumor cells and dermal fibroblasts was also reported (39). In our study, emp#2 peptide inhibited not only emmprin-mediated MMP-2 upregulation, but also the glioblastoma cell invasion augmented by interacting with fibroblasts.…”

Section: Discussionsupporting

confidence: 54%

Synthetic emmprin peptides inhibit tumor cell-fibroblast interaction-stimulated upregulation of MMP-2 and tumor cell invasion

Koga

Aoki²,

Sameshima³

et al. 2011

Int J Oncol

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Abstract. Stromal cells are the main source of matrix metalloproteinases (MMPs) in human carcinoma tissues. Emmprin is a glycosylated transmembrane protein containing two immunoglobulin (Ig) domains that is expressed in carcinoma cells and stimulates MMP production by adjacent stromal cells. The first Ig domain (ECI) of emmprin contains the biologically active site. We investigated whether synthetic peptides carrying a partial ECI sequence could inhibit emmprin activity. Only the second peptide (emp#2), which contains a putative N-glycosylation site sequence, inhibited emmprin-stimulated production of MMP-2 in co-cultures of fibroblasts and several different human tumor cells types, including carcinoma, sarcoma, melanoma, leukemia and glioma cells. Moreover, emp#2 significantly inhibited the invasive activity of glioblastoma cells promoted by interaction with fibroblasts. Perturbation of emmprin activity by this peptide may have potential therapeutic uses in the prevention of MMP-2-dependent cancer invasion.

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Section: Discussionsupporting

confidence: 54%

Synthetic emmprin peptides inhibit tumor cell-fibroblast interaction-stimulated upregulation of MMP-2 and tumor cell invasion

Koga

Aoki²,

Sameshima³

et al. 2011

Int J Oncol

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“…Cells were incubated at 37°C in a humidified atmosphere containing 5% CO 2 . Human umbilical vein endothelial cells (University of Alabama at Birmingham) were maintained in M199 media with 0.1 g/L heparin, 0.1 g/L endothelial cell growth factor, and 10% fetal bovine serum with antibiotics, as previously described (13). Normal dermal fibroblast isolation from primary culture and construction of the FaDu/siE cell lines by siRNA knockdown were also as described previously (13, 22).…”

Section: Methodsmentioning

confidence: 99%

“…Collagen assays were done as previously described (13) using type I collagen (BD Biosciences). FaDu, FaDu/siE, and normal dermal fibroblast cells were plated in 25 μL of DMEM with 0.1% bovine serum albumin in the center of each well and allowed to adhere for 2 h. Additional media with or without anti-EMMPRIN mAb, CNTO3899, was added to each well, and cells were incubated for 4 d. At the end of treatment, cells were removed and wells were stained with Coomassie blue (0.2%).…”

Section: Methodsmentioning

confidence: 99%

Anti-EMMPRIN Monoclonal Antibody as a Novel Agent for Therapy of Head and Neck Cancer

Dean¹,

Newman²,

Helman³

et al. 2009

Clinical Cancer Research

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Purpose: Extracellular matrix metalloprotease inducer (EMMPRIN) is a tumor surface protein that promotes growth and is overexpressed in head and neck cancer.These features make it a potential therapeutic target for monoclonal antibody (mAb)^based therapy. Because molecular therapy is considered more effective whendelivered with conventionalcytotoxic agents, anti-EMMPRINtherapy was assessed alone andin combination with external beam radiation. Experimental Design: Using a murine flank model, loss of EMMPRIN function was achieved by transfection with a small interfering RNA against EMMPRIN or treatment with a chimeric anti-EMMPRIN blocking mAb. Cytokine expression was assessed for xenografts, tumor cells, fibroblasts, and endothelial cells. Results: Animals treated with anti-EMMPRIN mAb had delayed tumor growth compared with untreated controls, whereas treatment with combination radiation and anti-EMMPRIN mAb showed the greatest reduction in tumor growth (P = 0.001). Radiation-treated EMMPRIN knockdown xenografts showed a reduction in tumor growth compared with untreated knockdown controls (P = 0.01), whereas radiation-treated EMMPRIN^expressing xenografts did not show a delay in tumor growth. Immunohistochemical evaluation for Ki67 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) resulted in a reduction in proliferation (P = 0.007) and increased apoptosis in anti-EMMPRIN mAb^treated xenografts compared with untreated controls (P = 0.087). In addition, we provide evidence that EMMPRIN suppression results in decreased interleukin 1h (IL-1h), IL-6, and IL-8 cytokine production, in vitro and in vivo. Conclusions: These data suggest that anti-EMMPRIN antibody inhibits tumor cell proliferation in vivo and may represent a novel targeted treatment option in head and neck squamous cell carcinoma.

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“…For example, in breast cancer, increased EMMPRIN expression results in immediate stimulation of VEGF and MMP production in tumor and stromal cells, and tumor-derived MMP can increase soluble VEGF or release biologically active angiogenic growth factors from matrix-bound complexes to modulate VEGF secretion in an MMP-dependent fashion in vivo. 26,[49][50][51] Recent findings also illustrate that EMMPRIN stimulates fibroblast-mediated tumor growth in head and neck squamous cell carcinoma in vivo, 52 and revealed that fibroblasts have a more profound influence on the development and progression of carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Expression of extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in pancreatic neoplasm and pancreatic stellate cells

Zhang¹,

Erkan²,

Abiatari³

et al. 2007

Cancer Biology & Therapy

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EMMPRIN (extracellular matrix metalloproteinase inducer, CD147) participates in the progression of various malignancies by stimulating the synthesis of specific matrix metalloproteinases (MMP) from peritumoral fibroblasts. In the present study, the expression and functional role of EMMPRIN was investigated in pancreatic neoplasm. QRT-PCR, immunohistochemistry, immunoblot, and ELISA analyses were used to analyze the expression, localization, and release of EMMRPIN. Silencing of EMMPRIN was performed using siRNA oligonucleotides, and functional consequences were assessed using growth assays, invasion assays, as well as MMP1/MMP2 and VEGF ELISA. EMMPRIN mRNA levels were 2.2-fold increased in pancreatic cancer (n = 52) and 2.0-3.5-fold increased in other pancreatic neoplasm (n = 105), but unchanged in chronic pancreatitis (n = 10) compared to normal pancreatic tissues (n = 9). Strong and predominantly membranous immunostaining was observed in the cancer cells and surrounding stromal cells. EMMPRIN serum levels were also significantly increased in pancreatic cancer patients (n = 44) (4.13 ± 0.28 ng/ml) with an AUC of 0.97 compared to healthy volunteers (n = 29) (0.95 ± 0.16 ng/ml; p < 0.0001) and with an AUC of 0.74 compared to chronic pancreatitis patients (n = 20) (2.98 ± 0.5 ng/ml; p = 0.0021). EMMPRIN silencing did not significantly affect anchorage-dependent or -independent growth of pancreatic cancer cells. In contrast, EMMPRIN silencing in pancreatic stellate cells slightly repressed VEGF and MMP2 levels but strongly increased pro-MMP1 expression under coculture conditions. In conclusion, Increased EMMPRIN expression is present in different pancreatic neoplasm, likely representing a tumor-specific reaction with the potential to modulate the tumor microenvironment rather than a mere reflection of an activated stroma.

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Extracellular Matrix Metalloprotease Inducer Stimulates Fibroblast‐Mediated Tumor Growth In Vivo

Abstract: As a cell surface expressed protein that promotes tumor growth and high expression in head and neck squamous cell carcinoma but not in normal tissue, EMMPRIN may be a good target for directed molecular therapy.

Cited by 12 publications

References 34 publications

Synthetic emmprin peptides inhibit tumor cell-fibroblast interaction-stimulated upregulation of MMP-2 and tumor cell invasion

Synthetic emmprin peptides inhibit tumor cell-fibroblast interaction-stimulated upregulation of MMP-2 and tumor cell invasion

Anti-EMMPRIN Monoclonal Antibody as a Novel Agent for Therapy of Head and Neck Cancer

Expression of extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in pancreatic neoplasm and pancreatic stellate cells

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