Evaluation of matrix metalloproteinase type IV-collagenases in serum of patients with tumors of the central nervous system (original) (raw)
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Expression and localization of 72 kDa type IV collagenase (MMP-2) in human malignant gliomas in vivo
Clinical & Experimental Metastasis, 1996
The 72 kDa type IV collagenase (gelatinase), a matrix metalloproteinase (MMP-2), has been proposed to potentiate the invasion and metastasis of malignant tumors. To determine the potential role of the MMP-2 in human gliomas and normal brain tissue, we examined the relative amounts of protein, mRNA, and distribution. Using gelatin zymography, densitometry, and an enzyme-linked immunosorbent assay for the quantitative determination of the MMP-2, we found that the enzyme's activity was significantly elevated in malignant astrocytomas, especially in glioblastoma multiforme, compared to low-grade glioma and normal brain tissues. As determined by Northern blot analysis, the amount of MMP-2 mRNA transcript was higher in anaplastic astrocytomas and glioblastoma multiforme tumors than in normal brain tissues or low-grade gliomas, a finding that was consistent with the amounts of MMP-2 protein detected in these tissues. Immunohistochemical studies demonstrated that MMP-2 was localized in tumor cells and vasculature cells of malignant astrocytomas. Staining intensity was clearly lower in low-grade astrocytomas, and immunoreactivity was very low or undetectable in normal brain astrocytes. The results suggest that expression of the MMP-2 is dramatically upregulated in malignant gliomas, correlating with the malignant progression of human gliomas in vivo.
Elevated Levels of Mr92,000 Type IV Collagenase during Tumor Growthin Vivo
Biochemical and Biophysical Research Communications, 1998
Our previous studies demonstrated that matrix metalloproteinase (MMP-9) levels were significantly higher in human glioblastoma tissue samples than in low-grade brain tumors and normal brain tissue (Rao et al., Cancer Res. 53, 2208 -2211, 1993). In the present study, we measured the levels of MMP-2 and MMP-9 during the growth of glial tumors in nude mice by intracerebral injection of glioblastoma cells. Using gelatin zymography, densitometry, and an enzyme-linked immunosorbent assay, we found that the enzyme activity and protein count of MMP-2 and MMP-9 were a respective 3-to 10-and 2-to 30-fold higher in tumors at day 14 and 28 than in normal tissue. Immunohistochemical staining for MMP-9 showed strong immunoreactivity in tumor cells and the staining intensity was much higher at day 28, compared to day 14. These results suggest that upregulation of MMP-9 plays a major role in the glioma tumor growth in vivo.
Expression and localization of 92 kDa type IV collagenase/gelatinase B (MMP-9) in human gliomas
Clinical & Experimental Metastasis, 1996
Matrix metalloproteinases play an important regulatory role in tissue morphogenesis, cell differentiation and motility, and tumor cell invasiveness. We have recently demonstrated elevated activity of the 92 kDa type IV collagenase (MMP-9) in human glioblastoma and in the present study examine the relative amounts of MMP-9 protein and mRNA in human gliomas and as well as the distribution of MMP-9 in human glioma tumors in vivo. Using an enzyme-linked immunosorbent assay for the quantitative determination of MMP-9 protein, we found that levels were significantly higher in malignant astrocytomas, especially in glioblastoma multiforme, than in normal brain tissues and low-grade gUomas. In addition, the amount of MMP-9 mRNA, as determined by northern blot analysis was higher in anaplastic astrocytomas and glioblastoma multiforme than in normal brain tissue and low-grade gliomas. Immunocytochemical staining for MMP-9 showed strong cytoplasmic immunoreactivity in the tumor cells and the proliferating endothelial cells of glioblastoma multiforme and anaplastic astrocytomas. The staining intensity was lower in low-grade astrocytomas, and was undetectable or very low in normal brain astrocytes. The results indicate that expression of MMP-9 is dramatically upregulated in highly malignant gliomas and correlates with the highly malignant progression of human gliomas in vivo, and support a role for the MMP-9 in facilitating the invasiveness seen in malignant gliomas in vivo.
Dual roles of tumour cells-derived matrix metalloproteinase 2 on brain tumour growth and invasion
British Journal of Cancer, 2017
Background: A previous study on a murine astrocytoma cell-line ALTS1C1 showed a highly invasive pattern similar to clinical anaplastic astrocytoma in vivo. This cell-line also expressed a high level of matrix metalloproteinase 2 (MMP2). This study aimed to verify the role of MMP2 in brain tumour progression. Methods: ALTS1C1 and MMP2 knockdown (MMP2kd) cells were inoculated intracranially, and tumour microenvironment was assessed by immunohistochemistry staining. Results: MMP2 expression was co-localised with CD31-positive cells at invading the tumour front and correlated with an invasive marker GLUT-1. The suppression of MMP2 expression prolonged the survival of tumour-bearing mice associated with tumours having smoother tumour margins, decreased Ki67-proliferating index, and down-regulated GLUT-1 antigen. Although the reduction of MMP2 expression did not alter the vessel density in comparison to parental ALTS1C1 tumours, vessels in MMP2kd tumours were less functional, as evidenced by the low ratio of pericyte coverage and reduction in Hoechst33342 dye perfusion. Conclusions: This study illustrated that tumour-derived MMP2 has at least two roles in tumour malignancy; to enhance tumour invasiveness by degrading the extracellular matrix and to enhance tumour growth by promoting vessel maturation and function. High-grade gliomas (HGG), including anaplastic oligodendroglioma, anaplastic astrocytoma, and glioblastoma multiforme (GBM), are the most aggressive brain tumours. HGG has distinctive characteristics, including immoderate proliferation, high invasiveness, anti-apoptosis, enhanced neovascularisation, and suppression of anti-tumour immunity. The survival rate for patients with HGG has remained to be low despite of the improved development of surgery, radiation therapy, and chemotherapy over the past two decades (Omuro and DeAngelis, 2013; Stupp et al, 2015; Blumenthal et al, 2017). The low curing rate for HGG is mainly due to the high invasive nature of these tumours, which prevents complete surgical resection and resistance to cytotoxic therapies (Giese et al, 2003). Secretion of proteolytic enzymes, such as serine, metallo-, and cysteine proteases, from tumour cells to degrade extracellular matrix (ECM) components and other natural barriers is the key feature for their invasiveness (Egeblad and Werb, 2002; Rao, 2003). Matrix metalloproteinases (MMPs) are a family of secreted, zincdependent endopeptidases and are involved in tissue-remodelling processes, including wound healing, embryo implantation, tumour invasion, metastasis, and angiogenesis (Stetler-Stevenson, 1990; Ray and Stetler-Stevenson, 1994; Rosenberg, 1995). Considerable evidences implicate that the MMPs, in particular MMP2 and MMP-9, are active contributors for the progression of malignant
Longitudinal prospective study of matrix metalloproteinase-9 as a serum marker in gliomas
Journal of Neuro-Oncology, 2011
The objective of this study was to evaluate if longitudinal measurements of serum matrix metalloproteinase-9 (MMP-9) correlated with disease status or survival in adults with gliomas. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. MMP-9 levels were determined by ELISA and correlated with radiographic disease status and survival. Forty-one patients with low-grade gliomas, 105 with anaplastic gliomas, and 197 with glioblastoma enrolled in this study from August 2002 to September 2008. A total of 1,684 serum samples (97.1% of all MMP-9 samples) had a matching MRI scan. No statistically significant association was observed between levels of serum MMP-9 and radiographic disease status in low-grade gliomas (P = 0.98), anaplastic gliomas (P = 0.39) or glioblastomas (P = 0.33). Among patients with glioblastoma, longitudinal increases in MMP-9 had a weak association with shorter survival (HR = 1.1 per each doubling in MMP-9 levels, 95% CI, 1.0-1.3, P = 0.04) but they were not independently associated with survival when adjusted for age, extent of resection, and performance status. Changes in serum MMP-9 were not associated with survival in the anaplastic glioma cohort. Serum MMP-9 showed no utility in determining glioma disease status and was not a clinically relevant prognostic marker of survival.
Matrix metalloproteinases and their biological function in human gliomas
International Journal of Developmental Neuroscience, 1999
AbstractÐGliomas, a type of devastating primary brain tumors, are distinct from other solid, nonneural primary neoplasms, in that they display extensive in®ltrative invasive behavior but seldom metastasize to distant organs. This invasiveness into the surrounding normal brain tissue makes gliomas a major challenge for clinical intervention. Total surgical resection of gliomas is not possible, and recurrence of tumor growth is common; mean survival time is 8±12 months. Although substantial progress has been made recently toward understanding the behavior of gliomas, the mechanisms that facilitate invasion are still poorly documented. Clues to the invasion process have been ascertained through clari-®cation of the key roles played by the extracellular matrix (ECM), cell-adhesion molecules and matrix degrading proteases. Serine proteases and metalloproteinases have been implicated in glioma tumor cell-invasion. Matrix metalloproteinases (MMPs) in particular can degrade almost all known ECM components and seem to play important roles in mediating glioblastoma tumor cell invasion. This review focuses on recent developments concerning the role of MMPs in the invasiveness of human gliomas. #
2006
We assessed the functional significance of tumor cell-associated matrix metalloproteinase i MMI'i-2 in extracellular matrix remodeling compared with that of the soluble enzyme by evaluating the contraction of threedimensional collagen lattices by human glioma U251.3 and n hrosai-coma HT-1080 cell lines. In this model, the constitutive synthesis and activation of the MMP-2 proenzyme were modulated by stable transfections of tumor cells with cDNA encoding membrane type 1-MMP iMTI-MMI'i. The efficiency of transfected cells in contracting collagen lattices was shown to be dependent on the MTl-MMP-mediated activation of MMP-2 accompanied by cell surface association of activated MMP-2, on the cell-matrix interactions controlled by collagen-specific integrins, and on the integrity of actin and microtubule cytoskeletons. Each one of these mechanisms was essential but was not sufficient by itself in accomplishing gel contraction by MTl-MMP-transfected cells. Both MMP-2 activation and...
Brain Tumor Pathology, 2011
Malignant gliomas are characterized by their invasiveness and angiogenesis. Matrix metalloproteinases (MMPs) degrade extracellular matrix and create a more permissive environment for cell invasion. We aimed to investigate for the presence of inter-and intratumoral heterogeneity in MMP-2 messenger RNA (mRNA) expression by means of quantitative analysis and to evaluate its prognostic impact in glioma patients. Representative sections from the center and periphery of tumors resected en bloc were taken fresh for study, stained with hematoxylin/eosin for histological evaluation, and immunohistochemically analyzed for Ki-67. MMP-2 mRNA expression was evaluated by real-time reverse transcriptase polymerase chain reaction (RT-PCR). There was MMP-2 expression in all analyzed tumors. By topographical dissection of surgical specimens, we found no differences in cell proliferation or density but significant differences with regard to MMP-2 mRNA expression between central and peripheral regions, being highest at the center of malignant gliomas. MMP-2 mRNA expression showed no prognostic influence on overall or disease-free survival. Our results demonstrate that MMP-2 is differentially expressed in central and peripheral regions of gliomas. Further studies are necessary to clarify the significance of these findings and their possible relevance in clinical practice.