Tissue plasminogen activator expression in meningiomas and glioblastomas

Goh, Keith Y.C.; Poon, Wai Sang; Chan, Danny; Ip, Chui Ping

doi:10.1016/j.clineuro.2004.09.010

Cited by 18 publications

(11 citation statements)

References 17 publications

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“…The PA/plasminogen system plays an important role in tumor invasion, a key step in tumor growth (Diaz et al, 2004; Goh et al, 2005; Rella et al, 1993; Stack et al, 1999). Since annA2KD clones had decreased activity for membrane-bound tPA (Figure 1E), we investigated whether annexin A2 could affect glioma invasion in vivo .…”

Section: Resultsmentioning

confidence: 99%

Annexin A2 Promotes Glioma Cell Invasion and Tumor Progression

Zhai¹,

Acharya²,

Gravanis³

et al. 2011

J. Neurosci.

107

101

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Gliomas are highly invasive, lethal brain tumors. Tumor-associated proteases play an important role in glioma progression. Annexin A2 is overexpressed in many cancers and correlates with increased plasmin activity on the tumor cell surface, which mediates degradation of extracellular matrix and promotes neoangiogenesis to facilitate tumor growth. In this study, we used two glioma cell lines, mouse GL261-EGFP and rat C6/lacZ, as well as stable clones transfected with an annexin A2 knockdown construct. We find that the annexin A2 knockdown decreased glioma cell migration in vitro and decreased membrane-bound plasmin activity. In vivo we injected the glioma cells into the rodent brain and followed glioma progression. Knockdown of annexin A2 in glioma cells decreased tumor size and slowed tumor progression, as evidenced by decreased invasion, angiogenesis and proliferation, as well as increased apoptosis in the tumor tissue of the annexin A2 knockdown group. Moreover, we report that the levels of expression of annexin A2 in human glioma samples correlate with their degree of malignancy. Taken together, our findings demonstrate that inhibition of annexin A2 expression in glioma cells could become a new target for glioma therapy.

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Section: Resultsmentioning

confidence: 99%

Annexin A2 Promotes Glioma Cell Invasion and Tumor Progression

Zhai¹,

Acharya²,

Gravanis³

et al. 2011

J. Neurosci.

107

101

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“…Upregulation of PDE1C has been associated with proliferation in other cell types through hydrolysis of cAMP and cGMP [63,64]. PRSS12 encodes a protease that can activate tissue plasminogen activator (tPA) [65], an enzyme that is highly expressed by glioma cells and has been suggested to promote invasion [66]. …”

Section: Discussionmentioning

confidence: 99%

Digital transcriptome profiling of normal and glioblastoma-derived neural stem cells identifies genes associated with patient survival

et al. 2012

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BackgroundGlioblastoma multiforme, the most common type of primary brain tumor in adults, is driven by cells with neural stem (NS) cell characteristics. Using derivation methods developed for NS cells, it is possible to expand tumorigenic stem cells continuously in vitro. Although these glioblastoma-derived neural stem (GNS) cells are highly similar to normal NS cells, they harbor mutations typical of gliomas and initiate authentic tumors following orthotopic xenotransplantation. Here, we analyzed GNS and NS cell transcriptomes to identify gene expression alterations underlying the disease phenotype.MethodsSensitive measurements of gene expression were obtained by high-throughput sequencing of transcript tags (Tag-seq) on adherent GNS cell lines from three glioblastoma cases and two normal NS cell lines. Validation by quantitative real-time PCR was performed on 82 differentially expressed genes across a panel of 16 GNS and 6 NS cell lines. The molecular basis and prognostic relevance of expression differences were investigated by genetic characterization of GNS cells and comparison with public data for 867 glioma biopsies.ResultsTranscriptome analysis revealed major differences correlated with glioma histological grade, and identified misregulated genes of known significance in glioblastoma as well as novel candidates, including genes associated with other malignancies or glioma-related pathways. This analysis further detected several long non-coding RNAs with expression profiles similar to neighboring genes implicated in cancer. Quantitative PCR validation showed excellent agreement with Tag-seq data (median Pearson r = 0.91) and discerned a gene set robustly distinguishing GNS from NS cells across the 22 lines. These expression alterations include oncogene and tumor suppressor changes not detected by microarray profiling of tumor tissue samples, and facilitated the identification of a GNS expression signature strongly associated with patient survival (P = 1e-6, Cox model).ConclusionsThese results support the utility of GNS cell cultures as a model system for studying the molecular processes driving glioblastoma and the use of NS cells as reference controls. The association between a GNS expression signature and survival is consistent with the hypothesis that a cancer stem cell component drives tumor growth. We anticipate that analysis of normal and malignant stem cells will be an important complement to large-scale profiling of primary tumors.

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“…Consistent with observations by Wallen and colleagues, we also found three species of tPA in the breast tumor tissues, heavy chain and a light chain of active tPA with a fragment of lower molecular weight. Lower molecular weight band may be a proteolytic degradation product which has been found in glioblastoma tumors [35]. Anti-ANX A2mAb treatment almost completely inhibited activated tc-tPA, but had no apparent effect on a lower molecular weight protein ( Fig.2A).…”

Section: Anti-anx A2mab Inhibited Tpa Conversion In the Human Breast mentioning

confidence: 87%

Long-term efficacy and downstream mechanism of anti-annexinA2 monoclonal antibody (anti-ANX A2 mAb) in a pre-clinical model of aggressive human breast cancer

et al. 2016

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There is considerable direct evidence that calcium binding protein ANX A2 is a potential target for treating aggressive breast cancer. The most compelling data are based on the finding of ANX A2 overexpression in aggressive triple negative human breast cancer (TNBC) cell lines and in human breast cancer tissues. Previously, we and others reported a unique role of ANX A2 in cancer invasion, including breast cancer. Moreover, we demonstrated that anti-ANX A2 mAb-mediated immunoneutralization of ANX A2 inhibited invasive human breast cancer growth in a xenograft model. We further evaluated the long-term effects of multiple treatments with anti-ANX A2 mAb and its mechanism of inhibition on human breast tumor growth. We now demonstrate that three treatments with anti-ANX A2 mAb led to significant inhibition of breast tumor growth in immunodeficient mice, and that the anti-tumor response was demonstrable from day 94. After treatment, we followed tumor growth for 172 days and demonstrated 67% inhibition of tumor growth without detectable adverse effects. Biochemical analysis demonstrated that anti-ANX A2 mAb treatment caused significant inhibition of conversion of tissue plasminogen activator (tPA) in the tumor microenvironment. This led to disruption of plasmin generation that consequently inhibited activation of MMP-9 and MMP-2. These results suggest that ANX A2 plays an important role in aggressive breast tumor growth by regulating proteolytic pathways in the tumor microenvironment. ANX A2 may represent a new target for the development of therapeutics for treatment of aggressive breast cancer.

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Tissue plasminogen activator expression in meningiomas and glioblastomas

Cited by 18 publications

References 17 publications

Annexin A2 Promotes Glioma Cell Invasion and Tumor Progression

Annexin A2 Promotes Glioma Cell Invasion and Tumor Progression

Digital transcriptome profiling of normal and glioblastoma-derived neural stem cells identifies genes associated with patient survival

Long-term efficacy and downstream mechanism of anti-annexinA2 monoclonal antibody (anti-ANX A2 mAb) in a pre-clinical model of aggressive human breast cancer

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