Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding

Yamaguchi, Noriko; Anand‐Apte, Bela; Lee, Margaret; Sasaki, Takako; Fukai, Naomi; Shapiro, Robert; Que, Ivo; Löwik, Clemens W.G.M.; Timpl, Rupert; Olsen, Bjørn R.

doi:10.1093/emboj/18.16.4414

Cited by 419 publications

(344 citation statements)

References 20 publications

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“…[21][22][23] In order to determine whether the altered behavior of HemEPCs, HemECs, and cbEPCs is concentration dependent, we carried out the migration assay with varying ES concentrations. This dose-response analysis showed no significant changes in the migration rate of the cells upon treatment with 1 ng/mL to 10 g/mL ES (data not shown).…”

Section: Es Induces Increased Adhesion Migration and Proliferation mentioning

confidence: 99%

“…As seen previously, basal and VEGF-induced migration of HDMECs was lower than HemECs, and VEGF-induced migration was inhibited by ES. 4,21,22 To determine if relative levels of well-known endothelial markers increased or decreased with growth in culture, RT-PCR (30 cycles) was performed on cells at passage 9 and passage 25: levels of CD31, CD34, VEGF-R2, VWF, and VE-cadherin did not change For personal use only. on April 2, 2019. by guest www.bloodjournal.org From in either HemEPCs or cbEPCs ( Figure 3B).…”

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confidence: 99%

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Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Khan

Melero‐Martin

et al. 2006

Blood

111

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Infantile hemangiomas are composed of endothelial cells (ECs), endothelial progenitor cells (EPCs), as well as perivascular and hematopoietic cells. Our hypothesis is that hemangioma-derived EPCs (HemEPCs) differentiate into the mature ECs that comprise the major compartment of the tumor. To test this, we isolated EPCs (CD133 ؉ /Ulex europeus-I ؉ ) and mature ECs (CD133 ؊ /Ulex europeus-I ؉ ) from proliferating hemangiomas and used a previously described property of hemangioma-derived ECs (HemECs), enhanced migratory activity in response to the angiogenesis inhibitor endostatin, to determine if HemEPCs share this abnormal behavior. Umbilical cord bloodderived EPCs (cbEPCs) were analyzed in parallel as a normal control. Our results show that HemEPCs, HemECs, and cbEPCs exhibit increased adhesion, migration, and proliferation in response to endostatin. This angiogenic response to endostatin was consistently expressed by HemEPCs over several weeks in culture, whereas HemECs and cbEPCs shifted toward the mature endothelial response to endostatin. Similar mRNAexpression patterns among HemEPCs, HemECs, and cbEPCs, revealed by microarray analyses, provided further indication of an EPC phenotype. This is the first demonstration that human EPCs, isolated from blood or from a proliferating hemangioma, are stimulated by an angiogenesis inhibitor. These findings suggest that EPCs respond differently from mature ECs when exposed to angiogenic or antiangiogenic signals. IntroductionInfantile hemangioma, the most common tumor of infancy, is characterized by rapid proliferation of the endothelial cells followed by slow spontaneous involution. 1 This transition from the proliferating phase to the involuting phase represents a gradient of cellular activity from unregulated proliferation to apoptosis. The molecular events that control the evolution of hemangioma remain obscure. Both intrinsic and extrinsic anomalies have been suggested to underlie the primary defect. [2][3][4][5][6] Recent studies showing that hemangioma-derived endothelial cells (HemECs) are clonal provide support for an intrinsic defect. 4,6 We and others have identified endothelial progenitor cells (EPCs) in hemangioma tissue and circulating blood of patients with hemangiomas, respectively. 7,8 These findings suggest that a hemangioma may arise from the clonal expansion of an EPC.An angioblastic origin for hemangiomas has been envisioned for over a century. In 1863, Virchow 9 questioned whether hemangiomas represented sequestered embryonic mesoderm. Pack and Miller 10 suggested that hemangiomas arise from the localized growth of angioblastic cells. Similarly, Malan 11 imagined hemangiomas as an activation of dormant angioblasts. Histologic examination of hemangioma ECs reveals an immature phenotype with large nuclei and scant cytoplasm. 12 During the rapid growth phase of hemangiomas, syncytial EC hyperplasia, with and without lumens, is seen. In the involuting phase, hyperplasia diminishes and mature vascular channels with defined lumens become prominent. 1 C...

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Section: Es Induces Increased Adhesion Migration and Proliferation mentioning

confidence: 99%

mentioning

confidence: 99%

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Khan

Melero‐Martin

et al. 2006

Blood

111

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“…Endostatin-XV and -XVIII obtained from bacteria were highly insoluble and contained many artificial disulfide-linked oligomers indicating improper folding of the proteins (16)(17)(18). Soluble monomeric endostatins could be obtained, however, from insect cells (4), yeast (17,19), and mammalian cells (20)(21)(22) but they may show subtle differences in conformation and posttranslational modifications. Domain NC1 could be also produced in mammalian cells and was shown to assemble noncovalently into a 100-kDa homotrimer as demonstrated for mouse collagens XVIII (20) and XV (21) and the C. elegans homolog (15).…”

Section: Structure and Binding Properties Of Nc1 Domains And Endostatinsmentioning

confidence: 99%

Structure and Function of Collagen‐Derived Endostatin Inhibitors of Angiogenesis

2002

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“…The total number of cells with nuclei that migrated per well was counted as described. 35 The assays were performed in quadruplicate.…”

Section: Cell Migration Assaysmentioning

confidence: 99%

Human chondrosarcoma secretes vascular endothelial growth factor to induce tumor angiogenesis and stores basic fibroblast growth factor for regulation of its own growth

Furumatsu

Nishida

Kawai

et al. 2001

Intl Journal of Cancer

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Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding

Cited by 419 publications

References 20 publications

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Structure and Function of Collagen‐Derived Endostatin Inhibitors of Angiogenesis

Human chondrosarcoma secretes vascular endothelial growth factor to induce tumor angiogenesis and stores basic fibroblast growth factor for regulation of its own growth

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