Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothelial cells

Enis, David R.; Shepherd, Benjamin R.; Wang, Yinong; Qasim, Asif; Shanahan, Catherine M.; Weissberg, Peter L.; Kashgarian, Michael; Pober, Jordan S.; Schechner, Jeffrey S.

doi:10.1073/pnas.0408357102

Cited by 92 publications

(76 citation statements)

References 29 publications

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“…87,88 We hypothesized that the most definitive method to assay for postnatal vasculogenesis would be to suspend putative EPCs in a scaffold, implant the scaffold, and assay for de novo human vessel formation. Following the work of Schechner et al, 89,90 we established a de novo EPC differentiation model in NOD/SCID mice. 39,89,90 In this model, collagen I gels are mixed with EPC test cells and implanted into immunodeficient mice.…”

Section: Epc Definition and Characterization -Endothelial Colony Formmentioning

confidence: 99%

“…Following the work of Schechner et al, 89,90 we established a de novo EPC differentiation model in NOD/SCID mice. 39,89,90 In this model, collagen I gels are mixed with EPC test cells and implanted into immunodeficient mice. Upon scaffold excision 14 days later, the number and histological characteristics of human vessels are examined.…”

Section: Epc Definition and Characterization -Endothelial Colony Formmentioning

confidence: 99%

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Working hypothesis to redefine endothelial progenitor cells

et al. 2007

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Section: Epc Definition and Characterization -Endothelial Colony Formmentioning

confidence: 99%

Section: Epc Definition and Characterization -Endothelial Colony Formmentioning

confidence: 99%

Working hypothesis to redefine endothelial progenitor cells

et al. 2007

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“…Blood vessel leakiness was studied using a protocol previously described by Enis et al 30 In brief, EC-Bcl-2 or EC-VC (2 Â 10 6 ) were mixed with 500 ml of matrigel and implanted in the right and left flank of SCID mice, respectively. After 10 days, 200 ml of FITC-dextran solution (25 mg/ml) was injected through the tail vein.…”

Section: Blood Vessel Leakiness Modelmentioning

confidence: 99%

Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion

Kumar

Polverini

2008

Laboratory Investigation

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Metastatic spread of tumor cells to vital organs is the major cause of mortality in cancer patients. Bcl-2, a key antiapoptotic protein, is expressed at high levels in a number of human tumors. We have recently shown that Bcl-2 is also overexpressed in tumor-associated blood vessels in head-and-neck cancer patients. Interestingly, enhanced Bcl-2 expression in tumor blood vessels is directly correlated with metastatic status of these cancer patients. In addition, endothelial cells (ECs) expressing Bcl-2 showed increased production of interleukin-8 (IL-8) resulting in significantly enhanced tumor cell proliferation and tumor cell invasion. Therefore, we hypothesized that Bcl-2 expression in tumorassociated ECs may promote tumor metastasis by enhancing tumor cell invasiveness and release in the circulation. To test our hypothesis, we coimplanted tumor cells along with ECs expressing Bcl-2 (EC-Bcl-2) in the flanks of SCID mice. Our results demonstrate that incorporation of EC-Bcl-2 in primary tumors significantly enhanced tumor cell metastasis to lungs and this EC-Bcl-2-mediated tumor metastasis was independent of primary tumor size. In addition, Bcl-2-mediated tumor metastasis directly correlated with increased tumor angiogenesis. Bcl-2 expression in ECs also promoted transendothelial cell permeability, blood vessel leakiness and tumor cell invasion. EC-Bcl-2-mediated tumor cell proliferation and tumor cell invasion were significantly mediated by IL-8. These results suggest that Bcl-2, when expressed at higher levels in tumor-associated ECs, may promote tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor cell invasiveness.

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“…However, the vascular component of tumors in these experimental models is provided by the murine host, and therefore is not adequate to study the effect of antiangiogenic strategies in human endothelium. 7 Conversely, long-lasting functional human blood vessels can be engineered in nude mice after implantation of human primary endothelial cells (ECs), [8][9][10][11][12][13] but they lack the influence of the tumor component. Coimplantation of tumor cells along with human ECs provides a best-suited model of tumor vasculature, 14 but it is not an accurate surrogate of the complex tumor microenvironment.…”

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confidence: 99%

Differential transplantability of human endothelial cells in colorectal cancer and renal cell carcinoma primary xenografts

Sanz

Cuesta

Salas

et al. 2009

Laboratory Investigation

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In vivo models of human tumor vasculature are essential for the study of tumor angiogenesis and validation of therapeutic targets. To date, however, few standardized animal models of human tumor angiogenesis have been characterized. It was recently shown that human renal cell and prostate carcinoma primary xenografts, established from biopsy specimens, contained vessels lined mainly by human endothelial cells 1 month after implantation in immunodeficient mice. We selected colorectal cancer (CRC) as a primary xenograft model and studied the response of the vascular compartment to the new microenvironment during the same lapse of time. Immunohistochemical analysis of the origin of endothelial cells demonstrated that, in contrast to the mentioned study, human endothelial cells were rapidly substituted by their murine counterparts (nearly 50% by day 10 after implantation). Apoptotic human endothelial cells could not be detected 10 days after implantation, suggesting that apoptosis is not the mechanism underlying their replacement. Interestingly, host endothelial cells were found to colocalize with human laminin, suggesting a colonization of human vascular basement membranes after human endothelial cell disappearance. To rule out that the differences observed between the fate of human vasculature in the CRC model and those previously reported were because of methodological aspects, we established renal cell carcinoma (RCC) primary xenografts using the same protocol. In clear contrast with CRC xenografts, vasculature within RCC xenografts was mostly of human origin 35 days after implantation. These results support the notion of angiogenic heterogeneity in malignant neoplasms. Elucidation of the molecular mechanisms that determine persistence or disappearance of human endothelial cells in different tumor contexts can help to shed light on the intimate regulation of the angiogenic process.

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Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothelial cells

Abstract: Implants of collagen-fibronectin gels containingangiogenesis ͉ cell transplantation ͉ endothelium

Cited by 92 publications

References 29 publications

Working hypothesis to redefine endothelial progenitor cells

Working hypothesis to redefine endothelial progenitor cells

Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion

Differential transplantability of human endothelial cells in colorectal cancer and renal cell carcinoma primary xenografts

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