Genes Expressed in Human Tumor Endothelium

Croix, Brad St.; Rago, Carlo; Velculescu, Victor E.; Traverso, Giovanni; Romans, Katharine; Montgomery, Elizabeth A.; Lal, Anita; Riggins, Gregory J.; Lengauer, Christoph; Vogelstein, Bert; Kinzler, Kenneth W.

doi:10.1126/science.289.5482.1197

Cited by 1,679 publications

(1,254 citation statements)

References 34 publications

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“…Moreover, by applying siRNA technology, we were able to demonstrate that signals emanated by IL-3 binding to its receptors are crucial for TEC proliferation and migration in vitro and for in vivo vessel formation as well. Blood vessels supplying tumors are considered unique as they differ from their normal counterparts with respect to morphology, pathophysiology, gene expression profile and outgrowth in the absence of growth factors (St Croix et al, 2000;Baluk et al, 2003). Considerable evidences have currently emerged sustaining the key role of Akt in driving TEC proangiogenic phenotype (Bussolati et al, , 2010.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike NECs in normal quiescent endothelium, TECs have a rapid turnover rate and therefore have been termed 'activated'. The 'activated' phenotype of TECs (Folkman, 2007) has been related to the expression of embryonic genes (St Croix et al, 2000) as well as genes regulating vessel growth, including the interleukin (IL)-3 gene (Bussolati et al, 2003). The inflammatory cytokine IL-3, released into tumor microenvironment (Dentelli et al, 2004), besides promoting survival and proliferation of mature endothelial cells (Dentelli et al, 1999), also acts as an endothelial differentiation factor for hematopoieticderived endothelial progenitor cells (EPCs) (Zeoli et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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IL-3 is a novel target to interfere with tumor vasculature

et al. 2011

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Angiogenesis inhibiting agents are currently integral component of anticancer therapy. However, tumors, initially responsive to anti-angiogenic drugs or vascular targeting agents, can acquire resistance. The limited clinical efficacy might result from the heterogeneous nature of tumors or alternatively from the unique phenotype of tumor vascular cells, widely diverse from so-called 'normal' endothelium. Hence, defining the molecular mechanisms driving this diversity might provide a rational basis to design combinatory therapies that should be more effective in avoiding resistance. Herein, we demonstrated that tumor-derived endothelial cells (TECs) isolated from breast and kidney carcinomas retained an endothelial phenotype, but outspread independently of growth factors. Applying small interfering RNA approach, we demonstrated that interleukin (IL)-3, but not vascular endothelial growth factor, released by TECs, supports their autocrine growth and promotes in vivo vessel formation and tumor angiogenesis. Meanwhile, we found that the expression of the membrane-bound kit ligand (mbKitL) depends on IL-3, and it is crucial for adhesion of endothelial progenitor cells (EPCs) and inflammatory cells to TECs. These events required Akt activation. Finally, the finding that depletion of the mbKitL prevented EPC and inflammatory cell trafficking into vascular microenvironment, indicates that, as in bone marrow, the mbKitL can act as a membrane/adhesion molecule for c-Kit-expressing cells. These data provide evidences that an IL-3 autocrine loop can drive a tumor endothelial switch and that targeting IL-3 might confer a significant therapeutic advantage to hamper tumor angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL-3 is a novel target to interfere with tumor vasculature

et al. 2011

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“…The expression of 12 genes increased at least twofold and the expression of 26 genes decreased at least twofold when ID4 was elevated (Supplementary Table S1). We systematically searched the literature for information about each of these genes, but the expression patterns and documented biologies associated with these genes did not suggest a function in angiogenesis, except in the case of matrix GLA protein (MGP) (St Croix et al, 2000;Bostrom et al, 2004).…”

Section: Identification Of a Potential Id4 Target Promoting Angiogenementioning

confidence: 99%

Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels

et al. 2010

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Inhibitor of differentiation-4 is highly expressed in glioblastoma multiforme (GBM). We report a novel proangiogenic function for inhibitor of differentiation-4 in the growth of glioblastoma xenografts. Tumor-derived cell cultures expressing elevated levels of ID4 produced enlarged xenografts in immunosuppressed mice that were better vascularized than corresponding control tumors and expressed elevated matrix GLA protein (MGP) that mediated enhanced tumor angiogenesis. Inhibition of MGP resulted in smaller and less vascularized xenografts. Our finding shows a novel function for ID4 in tumor angiogenesis, and identifies ID4 and MGP as possible therapeutic targets for GBM.

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“…In 2000, St. Croix et al found that the mRNA most upregulated in a sample of human colon cancer vascular cells was the message for endosialin (TEM1) 6061. Later, endosialin was found to be expressed in the vasculature and fibroblasts of human brain tumor specimens, including astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, meningioma, oligodendroglioma, ependymoma and carcinoma brain metastasis 6263.…”

Section: Sarcoma Targetsmentioning

confidence: 99%

Characteristics of human Ewing/PNET sarcoma models

Teicher¹,

Rouleau²,

Kruger³

et al. 2011

Annals of Saudi Medicine

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Ewing/PNET (peripheral neuroepithelioma) tumors are rare aggressive bone sarcomas occurring in young people. Rare-disease clinical trials can require global collaborations and many years. In vivo models that as accurately as possible reflect the clinical disease are helpful in selecting therapeutics with the most promise of positive clinical impact. Human Ewing/PNET sarcoma cell lines developed over the past 45 years are described. Several of these have undergone genetic analysis and have been confirmed to be those of Ewing/PNET sarcoma. The A673 Ewing sarcoma line has proven to be particularly useful in understanding the biology of this disease in the mouse. The chromosomal translocation producing the EWS/FLI1 fusion transcript characterizes clinical Ewing sarcoma. Cell lines that express this genetic profile are confirmed to be those of Ewing sarcoma. The A673 Ewing sarcoma line grows in culture and as a xenograft in immunodeficient mice. The A673 model has been used to study Ewing sarcoma angiogenesis and response to antiangiogenic agents. Many Ewing sarcoma clinical specimens express the cell surface protein endosialin. Several Ewing sarcoma cell lines, including the A673 line, also express cell surface endosialin when grown as subcutaneous tumor nodules and as disseminated disease; thus the A673 is a useful model for the study of endosialin biology and endosialin-directed therapies. With the advent of tools that allow characterization of clinical disease to facilitate optimal treatment, it becomes imperative, especially for rare tumors, to develop preclinical models reflecting disease subsets. Ewing PNET sarcomas are a rare disease where models are available.

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Genes Expressed in Human Tumor Endothelium

Cited by 1,679 publications

References 34 publications

IL-3 is a novel target to interfere with tumor vasculature

IL-3 is a novel target to interfere with tumor vasculature

Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels

Characteristics of human Ewing/PNET sarcoma models

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