Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 correlate with progression in human neuroblastoma

Ribatti, Doménico; Surico, Giammarco; Vacca, Angelo; Leonardis, Francesco De; Lastilla, Gaetano; Montaldo, Paolo G.; Rigillo, N; Ponzoni, Mirco

doi:10.1016/s0024-3205(00)01030-4

Cited by 58 publications

(38 citation statements)

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“…Perfusion-fixation of murine tumors with rhodamine and CD31 also documents a comparably complex vasculature mirroring that observed in human disease. Expression of VEGF has been reported in primary neuroblasts from human neuroblastoma, whereas expressions of VEGF-R1, VEGF-R2, MMP2, MMP9, and a-SMA are expressed in endothelial and periendothelial cells within the tumor microenvironment (5,6,11,(42)(43)(44)(45)(46). All of these proteins were also expressed in appropriate tumor and stromal elements from mice transgenic for TH-MYCN.…”

Section: Discussionmentioning

confidence: 99%

Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma

Chesler¹,

Goldenberg

Seales

et al. 2007

Cancer Research

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Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a wellestablished model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, A-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described watersoluble HPMA copolymer-TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumormicroenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma. [Cancer Res 2007;67(19):9435-42]

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Section: Discussionmentioning

confidence: 99%

Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma

Chesler¹,

Goldenberg

Seales

et al. 2007

Cancer Research

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“…Together with cysteine and serine proteases, MMPs have been suggested to play an important role in the proteolytic degradation of ECM (7,8,15). Within this group, MMP-2 and -9 are thought to have a pivotal role in tumor progression, angiogenesis, and invasion (8,13,14,21,22,24,28,36,37).…”

Section: Discussionmentioning

confidence: 99%

Expression of Matrix Metalloproteinases and Their Inhibitors in Medulloblastomas and Their Prognostic Relevance

Özen

Krebs

Hemmerlein³

et al. 2004

Clinical Cancer Research

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Purpose and Experimental Design:The cellular mechanisms leading to metastatic disease in medulloblastoma (MB), the most common malignant brain tumor in childhood, are mainly unknown. Recently, however, the involvement of matrix metalloproteinases (MMPs) has been suggested. We examined the expression and localization of four MMPs-MMP-2 and -9, membrane-type 1 and 2 MMP (MT1-and MT2-MMP)-and correlated the data with those for their main inhibitors, tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3), in 83 classical and 18 desmoplastic MBs.Results: Independent of the histological subtype, MMP-2 expression was found in a small percentage of tumors, whereas MMP-9 and MT1-or MT2-MMP were expressed in >75% of tumor samples. The expression of TIMP-1, -2, and -3, on the other hand, was found to depend on the histological subtype: TIMP-3 was often found in classical MB, whereas TIMP-2 was often expressed in desmoplastic MB (P ‫؍‬ 0.007-0.001). In addition, both TIMP-3 and -2 correlated significantly with the expression of all studied metalloproteinases except MMP-2. TIMP-1, detected only in classical MB in a low percentage, was the only TIMP that correlated with the expression of MMP-2. Kaplan-Meier estimation revealed significantly reduced long-term survival of patients with strong MMP expression in tumor samples. In multivariate logistic regression analysis, however, the prognosis was significantly determined only by clinical parameters.Conclusions: TIMP-3 and -2 expression is highly correlated with histological subtypes of MBs and strongly associated with the expression of certain MMPs. The expression of TIMPs and MMPs, however, does not determine prognosis independently of clinical parameters.

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“…MMP-9 has also been widely studied in both primary neuroblastoma tumors and in neuroblastoma cell lines (Ara et al, 1998;Ribatti et al, 1998Ribatti et al, , 2001Bjornland et al, 2001). In the current study, MMP-9 expression is increased in SHEP/Bcl-2 cells, but decreased in SHEP/N-Myc and SHEP/N-Myc/Bcl-2 cells, with no corresponding change in activity.…”

Section: Discussionmentioning

confidence: 99%

N-Myc and Bcl-2 coexpression induces MMP-2 secretion and activation in human neuroblastoma cells

Noujaim

Golen

et al. 2002

Oncogene

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Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 correlate with progression in human neuroblastoma

Cited by 58 publications

References 0 publications

Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma

Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma

Expression of Matrix Metalloproteinases and Their Inhibitors in Medulloblastomas and Their Prognostic Relevance

N-Myc and Bcl-2 coexpression induces MMP-2 secretion and activation in human neuroblastoma cells

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