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Angiopoietin-4 promotes glioblastoma progression by enhancing tumor cell viability and angiogenesis.

ABSTRACT: Glioblastoma multiforme (GBM) is a highly invasive and vascularized aggressive brain tumor. Less than 10% of GBM patients survive >5 years after diagnosis. Angiogenesis plays an important role in GBM growth, and antiangiogenesis-based therapies have shown clinical efficacy for GBM patients. Unfortunately, therapeutic resistance often develops in these patients, suggesting that GBM cells are capable of switching their dependency on one proangiogenic signaling pathway to an alternative one. Therefore, it is important to identify novel angiogenic factors that play essential roles in tumor angiogenesis and GBM progression. Angiopoietins (Ang-1, Ang-2, and Ang-4) are the ligands of the Tie-2 receptor tyrosine kinase (RTK). The roles of Ang-1 and Ang-2 in tumor angiogenesis have been established. However, little is known about how Ang-4 affects tumor angiogenesis and GBM progression and the mechanism underlying its effects. In our current study, we establish that Ang-4 is upregulated in human GBM tissues and cells. We show that, like endothelial cells, human GBM cells express Tie-2 RTK. We first establish that Ang-4 promotes in vivo growth of human GBM cells by promoting tumor angiogenesis and directly activating extracellular signal-regulated kinase 1/2 (Erk1/2) in GBM cells. Our results establish the novel effects of Ang-4 on tumor angiogenesis and GBM progression and suggest that this pro-GBM effect of Ang-4 is mediated by promoting tumor angiogenesis and activating Erk1/2 kinase in GBM cells. Together, our results suggest that the Ang-4-Tie-2 functional axis is an attractive therapeutic target for GBM.

SUBMITTER: Brunckhorst MK

PROVIDER: S-EPMC2940950 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Angiopoietin-4 promotes glioblastoma progression by enhancing tumor cell viability and angiogenesis.

Brunckhorst Melissa K MK Wang Hui H Lu Rong R Yu Qin Q

Cancer research 20100907 18

Glioblastoma multiforme (GBM) is a highly invasive and vascularized aggressive brain tumor. Less than 10% of GBM patients survive >5 years after diagnosis. Angiogenesis plays an important role in GBM growth, and antiangiogenesis-based therapies have shown clinical efficacy for GBM patients. Unfortunately, therapeutic resistance often develops in these patients, suggesting that GBM cells are capable of switching their dependency on one proangiogenic signaling pathway to an alternative one. Theref ...[more]

PMID: 20823154

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Project description:The angiopoietin (Angpt)-TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1-TIE2 signaling to destabilize the microvasculature during pathologic disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing ISH-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of patients with melanoma. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell-expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced reactive oxygen species (ROS) production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell-expressed ANGPT2 as an autocrine-positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of patients with melanoma. SIGNIFICANCE: This study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.

Dataset Information

Angiopoietin-4 promotes glioblastoma progression by enhancing tumor cell viability and angiogenesis.

Publications

Angiopoietin-4 promotes glioblastoma progression by enhancing tumor cell viability and angiogenesis.

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