Expression and clinical significance of EGFL7 in malignant glioma

Huang, Chunhai; Li, Xuejun; Zhou, Yi-zeng; Luo, Yong; Cui, Li; Yuan, Xianrui

doi:10.1007/s00432-010-0832-9

Cited by 50 publications

(60 citation statements)

References 21 publications

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“…Our finding underpins the importance of EGFL7 for vessel outgrowth in brain pathologies and is remarkable because only a few studies have addressed the question of how the EGFL7 protein is implicated in vascular diseases. Due to its putative role in angiogenesis, EGFL7 is assumed to play a role in tumor neoangiogenesis (eg, 2 global expression studies by Wu et al and Huang et al have implicated EGFL7 in hepatocellular carcinoma 37 and malignant glioma 38 ). In our work, we present evidence that EGFL7 expression relies on the grade of vascularization of human pathologies rather than on tumorigenicity; therefore, EGFL7-targeting agents such as EGFL7-blocking antibodies may prove useful for the treatment of multiple diseases beyond the cure of neoplasms.…”

Section: Discussionmentioning

confidence: 99%

EGFL7 ligates αvβ3 integrin to enhance vessel formation

Nikolić

Stanković

Bicker

et al. 2013

Blood

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Key Points• EGFL7 promotes angiogenesis via its interaction with integrin a v b 3 .• EGFL7 is involved in physiological and pathological angiogenesis.Angiogenesis, defined as blood vessel formation from a preexisting vasculature, is governed by multiple signal cascades including integrin receptors, in particular integrin a V b 3 . Here we identify the endothelial cell (EC)-secreted factor epidermal growth factorlike protein 7 (EGFL7) as a novel specific ligand of integrin a V b 3 , thus providing mechanistic insight into its proangiogenic actions in vitro and in vivo. Specifically, EGFL7 attaches to the extracellular matrix and by its interaction with integrin a V b 3 increases the motility of EC, which allows EC to move on a sticky underground during vessel remodeling. We provide evidence that the deregulation of EGFL7 in zebrafish embryos leads to a severe integrin-dependent malformation of the caudal venous plexus, pointing toward the significance of EGFL7 in vessel development. In biopsy specimens of patients with neurologic diseases, vascular EGFL7 expression rose with increasing EC proliferation. Further, EGFL7 became upregulated in vessels of the stroke penumbra using a mouse model of reversible middle cerebral artery occlusion. Our data suggest that EGFL7 expression depends on the remodeling state of the existing vasculature rather than on the phenotype of neurologic disease analyzed. In sum, our work sheds a novel light on the molecular mechanism EGFL7 engages to govern physiological and pathological angiogenesis. (Blood. 2013;121(15):3041-3050)

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Section: Discussionmentioning

confidence: 99%

EGFL7 ligates αvβ3 integrin to enhance vessel formation

Nikolić

Stanković

Bicker

et al. 2013

Blood

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“…In colon carcinoma and in glioma, high expression levels of Egfl7 transcripts were associated with higher tumor grades (11,13) and with higher microvascular density in the case of glioma (13). However, since there was no separate analysis of expression of Egfl7 in endothelial, stromal and tumor cells in these studies and since Egfl7 is highly expressed in endothelial cells, it is most probable that these correlations were at least partly due to the high vascularization of advanced tumors, as seen in gliomas (13). These analyses need to be complemented with a histologic identification, such as that performed here.…”

Section: Discussionmentioning

confidence: 99%

“…Egfl7 is expressed by cancer cells of human hepatocarcinoma and high levels of expression are correlated with poor survival (12). In a series of human gliomas, high levels of Egfl7 in tumor tissue correlate with higher tumor grade, Ki67 index and microvascular density (13). Here, we performed the first study of the expression of Egfl7 transcripts levels and protein localization in human breast cancer lesions.…”

Section: Introductionmentioning

confidence: 99%

Expression of Egfl7 correlates with low-grade invasive lesions in human breast cancer

Philippin-Lauridant

Baranzelli

Samson

et al. 2013

International Journal of Oncology

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Abstract. Egfl7 (VE-statin) is specifically expressed by endothelial cells of normal tissues but its expression is deregulated in human cancers. Analysis of expression of Egfl7 protein and transcripts in 211 human breast cancer samples shows that Egfl7 is strongly expressed by breast tumor cells. Egfl7 expression is significantly higher in invasive ductal than in invasive lobular carcinoma. Expression of Egfl7 transcripts is also higher in lower SBR grade lesions and in lesions which are not associated with lymph node invasion. Within the invasive ductal carcinoma sub-population, expression of Egfl7 transcripts is correlated with the SBR score and with the ER + status. High transcript and Egfl7 protein levels significantly correlate with the absence of axillary lymph node invasion. In lymph nodes, the levels of Egfl7 are correlated with the histological type of the primary lesions; they are higher in ductal than in lobular carcinoma. Egfl7 expression is thus associated with better prognosis factors and with the absence of lymph node invasion in human breast cancer lesions.

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“…EGFL7 is a secreted protein produced by nascent tumor blood vessels as well as vessels in other proliferating tissues, but it is absent or expressed at low levels in healthy quiescent vessels as well as many nonvascular cell types (7)(8)(9)(10)(11). Upon secretion, EGFL7 becomes tightly associated with the perivascular extracellular matrix and supports EC adhesion and migration (10,12).…”

Section: Introductionmentioning

confidence: 99%

Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy

Johnson¹,

Huseni²,

Smyczek³

et al. 2013

J. Clin. Invest.

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Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix-associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress-induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF-mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non-small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor-bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials.

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Expression and clinical significance of EGFL7 in malignant glioma

Abstract: Our data suggest that EGFL7 expression is a novel predictive factor for the clinical progression of malignant glioma, and may constitute a therapeutic target for anti-angiogenesis therapy in patients with the disease.

Cited by 50 publications

References 21 publications

EGFL7 ligates αvβ3 integrin to enhance vessel formation

EGFL7 ligates αvβ3 integrin to enhance vessel formation

Expression of Egfl7 correlates with low-grade invasive lesions in human breast cancer

Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy

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