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Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM.

ABSTRACT: Glioblastoma multiforme (GBM) is one the most aggressive brain tumors due to the fast and invasive growth that is partly supported by the presence of extensive neovascularization. The matrix metalloproteinase MMP-2 has been associated with invasive and angiogenic properties in gliomas and is a marker of poor prognosis. Since MMP-2 is expressed in both tumor cells and endothelial cells in GBM, we generated genetically engineered MMP-2 knockout (MMP-2ko) GBM to examine the importance of the spatial expression of MMP-2 in tumor and/or normal host-derived cells. MMP-2-dependent effects appeared to be dose-dependent irrespective of its expression pattern. GBM completely devoid of MMP-2 exhibited markedly increased vascular density associated with vascular endothelial growth factor receptor 2 (VEGFR2) activation and enhanced vascular branching and sprouting. Surprisingly, despite the high vascular density, tumor cells were more prone to apoptosis, which led to prolonged survival of tumor-bearing mice, suggesting that the increased vascularity is not functional. Congruently, tumor vessels were poorly perfused, exhibited lower levels of VEGFR2, and did not undergo proper maturation because pericytes of MMP-2ko tumors were not activated and were less abundant. As a result of impaired and dysfunctional angiogenesis, MMP-2ko GBM became more invasive, predominantly by migrating along blood vessels into the brain parenchyma.

SUBMITTER: Du R

PROVIDER: S-EPMC2563048 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM.

Du Rose R Petritsch Claudia C Lu Kan K Liu Patty P Haller Anna A Ganss Ruth R Song Hanqiu H Vandenberg Scott S Bergers Gabriele G

Neuro-oncology 20080321 3

Glioblastoma multiforme (GBM) is one the most aggressive brain tumors due to the fast and invasive growth that is partly supported by the presence of extensive neovascularization. The matrix metalloproteinase MMP-2 has been associated with invasive and angiogenic properties in gliomas and is a marker of poor prognosis. Since MMP-2 is expressed in both tumor cells and endothelial cells in GBM, we generated genetically engineered MMP-2 knockout (MMP-2ko) GBM to examine the importance of the spatia ...[more]

PMID: 18359864

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Project description:The biological and molecular events that regulate the invasiveness of breast tumour cells need to be further revealed to develop effective therapies that stop breast cancer from expanding and metastasising.Human tissue samples of invasive breast cancer and normal breast, as well as breast cancer cell lines, were evaluated for protein kinase D (PKD) expression, to test if altered expression could serve as a marker for invasive breast cancer. We further utilised specific PKD1-shRNA and a system to inducibly-express PKD1 to analyse the role of PKD1 in the invasive behaviour of breast cancer cell lines in two-dimensional (2D) and three-dimensional (3D) culture. Invasive behaviour in breast cancer cell lines has been linked to matrix metalloproteinases (MMPs), so we also determined if PKD1 regulates the expression and activity of these enzymes.We found that the serine/threonine kinase, PKD1, is highly expressed in ductal epithelial cells of normal human breast tissue, but is reduced in its expression in more than 95% of all analysed samples of human invasive breast tumours. Additionally, PKD1 is not expressed in highly invasive breast cancer cell lines, whereas non-invasive or very low-invasive breast cancer cell lines express PKD1. Our results further implicate that in MDA-MB-231 cells PKD1 expression is blocked by epigenetic silencing via DNA methylation. The re-expression of constitutively-active PKD1 in MDA-MB-231 cells drastically reduced their ability to invade in 2D and 3D cell culture. Moreover, MCF-7 cells acquired the ability to invade in 2D and 3D cell culture when PKD1 expression was knocked-down by shRNA. PKD1 also regulated the expression of breast cancer cell MMPs, MMP-2, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, MMP-14 and MMP-15, providing a potential mechanism for PKD1 mediation of the invasive phenotype.Our results identify decreased expression of the PKD1 as a marker for invasive breast cancer. They further suggest that the loss of PKD1 expression increases the malignant potential of breast cancer cells. This may be due to the function of PKD1 as a negative regulator of MMP expression. Our data suggest re-expression of PKD1 as a potential therapeutic strategy.

Project description:BackgroundIonizing radiation (IR) in combination with microtubule stabilizing agents (MSA) is a promising combined treatment modality. Supra-additive treatment responses might result from direct tumor cell killing and cooperative indirect, tumor cell-mediated effects on the tumor microenvironment. Here we investigated deregulation of matrix metalloproteinase (MMP) activity, as an important component of the tumor microenvironment, by the combined treatment modality of IR with the clinically relevant MSA patupilone.MethodsExpression, secretion and activity of MMPs and related tissue inhibitors of metalloproteinases (TIMPs) were determined in cell extracts and conditioned media derived from human fibrosarcoma HT1080 and human glioblastoma U251 tumor cells in response to treatment with IR and the MSA patupilone. Treatment-dependent changes of the invasive capacities of these tumor cell lines were analysed using a Transwell invasion assay. Control experiments were performed using TIMP-directed siRNA and TIMP-directed inhibitory antibodies.ResultsEnzymatic activity of secreted MMPs was determined after treatment with patupilone and irradiation in the human fibrosarcoma HT1080 and the human glioblastoma U251 tumor cell line. IR enhanced the activity of secreted MMPs up to 2-fold and cellular pretreatment with low dose patupilone (0.05-0.2 nM) counteracted specifically the IR-induced MMP activity. The cell invasive capacity of HT1080 and U251 cells was increased after irradiation with 2 Gy by 30% and 50%, respectively, and patupilone treatment completely abrogated IR-induced cell invasion. Patupilone did not alter the level of MMP expression, but interestingly, the protein level of secreted TIMP-1 and TIMP-2 was lower after combined treatment than after irradiation treatment alone. Furthermore, siRNA depletion of TIMP-1 or TIMP-2 prevented IR-mediated induction of MMP activity and cell invasion.ConclusionsThese results indicate that patupilone counteracts an IR-induced MMP activation process by the reduction of secreted TIMP-1 and TIMP-2 proteins, which are required for activation of MMPs. Since IR-induced MMP activity could contribute to tumor progression, treatment combination of IR with patupilone might be of great clinical benefit for tumor therapy.

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Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM.

Publications

Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM.

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