Angiopoietin-2 Is Implicated in the Regulation of Tumor Angiogenesis

Yu, Qin; Stamenkovic, Ivan

doi:10.1016/s0002-9440(10)63998-3

Cited by 100 publications

(75 citation statements)

References 31 publications

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“…This underlines the importance of Angs in vascular morphogenesis induced by Matrigel. 28,29 To verify if this was the case, we evaluated the cord formation under the presence of nNL-StCs-CM and HCC-StCs-CM derived from patient 9 that contained a good amount of Ang-1 and 2 (Table 1). In addition, we also added antibodies anti-Tie2 that block Ang-1 receptor activity.…”

Section: Hcc-stcs Display a Reduced Angiogenic Potential And Capacitymentioning

confidence: 99%

Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma

Balzarini

Benetti

Invernici

et al. 2012

Laboratory Investigation

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Hepatocellular carcinoma (HCC) is a very angiogenic and malignant cancer. Conventional chemotherapy is poorly effective because of the abnormal structural organization of HCC-infiltrating vessels. In previous work, we demonstrated that HCC angiogenesis is driven by transforming growth factor beta-1(TGF-b1)/CD105 axis, stimulating liver-derived microvascular endothelial cells (Ld-MECs) migration. As TGF-b1 also affects mural cells (MCs) recruitment and maturation, we asked whether it may contribute to HCC-induced vascular abnormalities. HCC and adjacent non-neoplastic liver (nNL) biopsies obtained from 12 patients were analyzed by immunohistochemistry for angiogenic markers CD105, TGF-b1, CD44 and vascular endothelial growth factor-a (VEGFa) and for MC markers NG2, a-smooth muscle actin (aSMA) and neural cell adhesion molecule (NCAM). The same markers were also investigated by immunocytochemistry on cultured HCC-derived stromal cells (HCC-StCs) and nNL-derived StCs (nNL-StCs) isolated from the same liver biopsies. Angiogenic factors released by StCs were analyzed by ELISA and the interaction between StCs and Ld-MECs by adhesion assay. Compared with nNL, HCC biopsies showed increased angiogenic markers and aSMA that was localized in vessels. By contrast, NG2 and NCAM were substantially localized in tumor cells but absent in vessels and stroma. Cultured HCCStCs showed less expression of NG2, aSMA and NCAM. They also demonstrated a lower capacity to release angiogenic factors and adhered on Ld-MECs. HCC-StCs and nNL-StCs treated with TGF-b1 or with of HepG2 (a human hepatoma cell line) derived conditioned medium (CM), down-modulated NCAM expression, whereas anti-NCAM antibodies significantly reduced the adhesion of StCs to Ld-MECs. By further blocking TGF-b1 with anti-TGF-b1 antibodies or with Ly-364947 (a specific inhibitor TGF-b1-receptor) adhesion to Ld-MECs and NCAM expression respectively was partially restored. TGF-b1 contributes to HCC-induced vascular alterations by affecting the interaction between HCC-StCs and Ld-MECs through a down-modulation of NCAM expression. A growing tumor recruits new blood vessels to ensure a sufficient quantity of nutrients and oxygen necessary for cancer cell survival and proliferation.1 During this process, neoformed capillaries undergo abnormal maturation 2 and vascular abnormalities are often observed in tumor, mainly involving either the composition of the basement membrane or mural cells (MCs) content. 3,4 To this regard, pericytes and smooth muscle cells (SMCs) are fundamental to determine an

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Section: Hcc-stcs Display a Reduced Angiogenic Potential And Capacitymentioning

confidence: 99%

Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma

Balzarini

Benetti

Invernici

et al. 2012

Laboratory Investigation

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“…49 However, the weight of evidence indicates that Ang-2 antagonism of Tie-2 in the absence of VEGF has more severe effects on endothelium, causing apoptosis and regression. 50,51 Ang-2-mediated vascular pathology could initiate the hypoxic conditions that precede tumor cell migration and pseudopalisade formation in GBM.…”

Section: Mechanisms Of Vascular Pathology In Gbm Vascular Regressionmentioning

confidence: 99%

Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma

Brat

Meir

2004

Laboratory Investigation

294

276

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Glioblastoma (GBM) has explosive biologic properties with rapid clinical progression leading to death. Its distinguishing pathologic features, necrosis with surrounding pseudopalisades and microvascular hyperplasia, are believed to be instrumental to its accelerated growth. Microvascular hyperplasia arises in response to the secretion of proangiogenic factors by hypoxic pseudopalisades and allows for peripheral neoplastic expansion. Mechanisms underlying necrosis and hypoxia remain obscure, but vaso-occlusive and prothrombotic contributions could be substantial. Recent investigations on the origin of pseudopalisades suggest that this morphologic phenomenon is created by a tumor cell population actively migrating away from a central hypoxic region and that, in at least a significant subset, hypoxia-induced migration appears due to vasoocclusion caused by intravascular thrombosis. Both vascular endothelial growth factor induced vascular permeability to plasma coagulation factors and the increased neoplastic expression of tissue factor likely contribute to a prothrombotic state favoring intravascular thrombosis. In addition to prothrombotic mechanisms, vaso-occlusion could also result from angiopoietin-2-mediated endothelial cell apoptosis and vascular regression, which follows neoplastic co-option of native vessels in animal models of gliomas. Vasoocclusive and prothrombotic mechanisms in GBM could readily explain the presence of pseudopalisades and coagulative necrosis in tissue sections, the emergence of central contrast enhancement and its rapid peripheral expansion on neuroimaging, and the dramatic shift to an accelerated rate of clinical progression. Since the hypoxic induction of angiogenesis appears to support further neoplastic growth, therapeutic targeting of the underlying vascular pathology and thrombosis could provide a new means to prolong time to progression.

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“…Reverse transcriptase-polymerase chain reaction (RT-PCR), expression constructions and deletion mutagenesis RT-PCR was performed as described (Yu and Stamenkovic, 2001) using total RNAs from mouse Tr6BC1 schwannoma cells and two primer pairs corresponding to 24 nucleotides at the 5 0 and 3 0 extremities of the coding sequences of mouse merlin isoform I or II (under the accession numbers NM_010898 and L27105, respectively). Full-length merlin isoform I was obtained by PCR using mouse brain cDNA as template with Pfu DNA polymerase (Stratagene, La Jolla, CA, USA) and a pair of primers corresponding to 24 nucleotides at the 5 0 and 3 0 ends of the coding sequence of the molecule (NM_010898).…”

Section: Cells and Reagentsmentioning

confidence: 99%

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Bai

et al. 2006

Oncogene

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Mutation or loss of expression of merlin is responsible for neurofibromatosis type 2 (NF2), which is characterized by the development of schwannomas and other tumors of the nervous system. Like the ERM (ezrin-radixin-moesin) proteins, merlin interacts with CD44, a cell-surface receptor for hyaluronan (HA) that promotes tumorigenesis. However, the relationship between merlin and CD44 and the mechanism by which merlin exerts its tumorsuppressor function have not been elucidated. In the present study, we show that increased expression of wildtype merlin in Tr6BC1 schwannoma cells inhibits HA binding to CD44. Furthermore, we demonstrate that the residues required for this inhibitory effect and the interaction between CD44 and merlin lie within the first 50 amino acids of merlin. Overexpression of merlin inhibited subcutaneous growth of Tr6BC1 cells in immunocompromised Rag1 mice. In contrast, knocking down expression of endogenous merlin promoted tumor cell growth, as did overexpression of a merlin deletion mutant (merlinDel-1) that lacks the first 50 amino acids but not of other NH 2 -terminal deletion mutants. Together, our results demonstrate that inhibition of the CD44-HA interaction contributes to the tumor-suppressor function of merlin, and they suggest that merlin inhibits tumor growth, at least in part, by negatively regulating CD44 function.

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Angiopoietin-2 Is Implicated in the Regulation of Tumor Angiogenesis

Cited by 100 publications

References 31 publications

Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma

Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma

Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

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