Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

Lu, Kan V.; Jong, Kimberly A.; Rajasekaran, Ayyappan K.; Cloughesy, Timothy F.; Mischel, Paul S.

doi:10.1038/sj.labinvest.3700003

Cited by 60 publications

(46 citation statements)

References 18 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In fact, it has been shown that their expression is significantly increased in inflammation (Shamamian et al, 2001) and in tumour invasiveness and metastatisation (Turck et al, 1996) processes. Metalloproteinases are in turn regulated by inhibitory molecules (Goldman and Shalev, 2004); the balance between the two molecular families being critical for control of proteolysis (Lu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

et al. 2006

View full text Add to dashboard Cite

Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.

show abstract

Section: Discussionmentioning

confidence: 99%

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Gelatin zymography was performed as described previously, with modifications (Lu et al, 2004). Samples were mixed with zymogram sample buffer and loaded onto 8% polyacrylamide gels containing 0.1% gelatin.…”

Section: Gelatin Zymographymentioning

confidence: 99%

Carcinoma cells induce lumen filling and EMT in epithelial cells by soluble E-cadherin-mediated activation of EGFR

Patil

D'Ambrosio

Inge

et al. 2015

Journal of Cell Science

View full text Add to dashboard Cite

In epithelial cancers, carcinoma cells coexist with normal cells. Although it is known that the tumor microenvironment (TME) plays a pivotal role in cancer progression, it is not completely understood how the tumor influences adjacent normal epithelial cells. In this study, a three-dimensional co-culture system comprising non-transformed epithelial cells (MDCK) and transformed carcinoma cells (MSV-MDCK) was used to demonstrate that carcinoma cells sequentially induce preneoplastic lumen filling and epithelial-mesenchymal transition (EMT) in epithelial cysts. MMP-9 secreted by carcinoma cells cleaves cellular E-cadherin (encoded by CDH1) from epithelial cells to generate soluble E-cadherin (sE-cad), a pro-oncogenic protein. We show that sE-cad induces EGFR activation, resulting in lumen filling in MDCK cysts. Long-term sE-cad treatment induced EMT. sE-cad caused lumen filling by induction of the ERK signaling pathway and triggered EMT through the sustained activation of the AKT pathway. Although it is known that sE-cad induces MMP-9 release and consequent EGFR activation in tumor cells, our results, for the first time, demonstrate that carcinoma cells can induce sE-cad shedding in adjacent epithelial cells, which leads to EGFR activation and the eventual transdifferentiation of the normal epithelial cells.

show abstract

“…But, at lower concentrations, TIMP-2 is also essential for the efficient activation of pro-MMP-2. Due to the dual nature of TIMP-2, a small shift in the balance between TIMP and MMP levels may greatly modulate the invasive phenotype in tumor cells (10).…”

Section: Introductionmentioning

confidence: 99%

Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma

Uchibori¹,

Nishida²,

Nagasaka³

et al. 2006

Int J Oncol

View full text Add to dashboard Cite

Abstract. Numerous studies have demonstrated a correlation of matrix metalloproteinase (MMP) overexpression with the prognosis of various kinds of cancer. The current study investigated whether the expression of MMPs is correlated with the prognosis of osteosarcoma. Expression levels of MMP-2, -9, MT1-MMP and TIMP-2 were examined immunohistochemically in samples from 47 patients with osteosarcoma. Correlation of the positivity of staining with prognosis was analyzed with the Kaplan-Meier method, and statistically analyzed with log-rank test. Co-localization of MMP-2, MT1-MMP and TIMP-2 was determined by double staining with fluorescence-conjugated antibodies. Activities of gelatinases in representative tissues were examined with gelatin zymography. MMP-2 was expressed strongly in 60% of cases (28/47), and MMP-9, MT1-MMP and TIMP-2 was strongly positive in 61% (29/47), 45% (21/47), and 91% (43/47), respectively. Increased MT1-MMP expression was associated significantly with poor prognosis in overall survival (P=0.0480). In cases of overexpression for both MMP-2 and MT1-MMP, there was a tendency for poor prognosis (P=0.0969). In 36 cases who underwent neoadjuvant chemotherapy, wide resection of the tumors and post-operative adjuvant chemotherapy, increased expression of MT1-MMP resulted in a significant negative prognostic factor for disease-free survival (P=0.0143). Also, co-overexpression of MT1-MMP and MMP-2 showed a tendency to correlate to the reduced disease-free survival (P=0.0502). Increased gelatinase activity was observed in tissues of co-overexpression of MT1-MMP and MMP-2. The results of this study demonstrate the correlation of MT1-MMP expression and the oncological outcome of osteosarcoma patients, suggesting the prognostic significance of these proteins in osteosarcoma patients. IntroductionOsteosarcoma is the most frequent primary malignant bone tumor in children and adolescents (1-3). In the last two decades, the combination of chemotherapy with surgical treatment dramatically improved the clinical outcome of the patients with osteosarcoma. However, there are still a certain number of patients who do not benefit from these improvements. Attempts have been made to identify prognostic factors to predict outcome, and to determine those patients who should undergo more intensive treatment, however, further work is required.Malignant tumor cell invasion is believed to involve a complex series of integrated events consisting of tumor cell adhesion, extracellular matrix (ECM) proteolysis, and cell migration within the microenvironment (4). Among the proteases contributing to ECM degradation, matrix metalloproteases (MMPs) are thought to play significant roles in tumor invasion and metastasis (5,6). Synthesized as either secreted or membrane-bound latent enzymes, MMPs require proteolytic activation involving cleavage of propeptide domain to exhibit enzymatic activity (7). Cell-mediated pro-MMP-2 activation involves cleavage by MT1-MMP on cell membranes (8,9). The activity of these MMPs is regulated by the...

show abstract

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

Cited by 60 publications

References 18 publications

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

Carcinoma cells induce lumen filling and EMT in epithelial cells by soluble E-cadherin-mediated activation of EGFR

Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma

Contact Info

Product

Resources

About