Vascular Morphogenesis and Differentiation after Adoptive Transfer of Human Endothelial Cells to Immunodeficient Mice

Skovseth, Dag K.; Yamanaka, Takeshi; Brandtzæg, Per; Butcher, Eugene C.; Haraldsen, Guttorm

doi:10.1016/s0002-9440(10)61110-8

Cited by 30 publications

(26 citation statements)

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“…Other techniques for producing microvessels from cultured ECs that have been described (10,12) use Matrigel, a proangiogenic, incompletely defined tumor matrix with controversial effects on vessel formation (25). Such models are unlikely to be suitable for long-duration functional studies due to apoptosis of the human ECs and ingrowth of murine vessels.…”

Section: Discussionmentioning

confidence: 99%

“…Such EC-based neovascularization strategies may be enhanced by genetic manipulation of the cells before implantation, e.g., by expressing antiapoptotic proteins or factors that enhance vessel growth and maturation (8,9). Although several techniques of EC implantation (using extracellular matrices of Matrigel or type I collagen) have been described (10)(11)(12), the resulting vessels have not been extensively characterized. We previously reported that implantation of collagen͞fibronectin gels containing human umbilical vein endothelial cells (HUVECs) retrovirally transduced with the antiapoptotic gene Bcl-2 (but not control-transduced ECs) efficiently recruit host SM cells to form chimeric microvessels within the abdominal wall of immunodeficient mice.…”

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confidence: 99%

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

Enis

Shepherd

Wang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Enis

Shepherd

Wang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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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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“…In the absence of endostatin, human endothelial cells suspended in Matrigel form complex human vessels that make xenogeneic contact with the murine vascular system, carry murine blood, and recruit perivascular ␣-smooth muscle actin-positive cells. 44 However, systemic delivery of yeast-derived, recombinant human endostatin leading to serum levels of 30 to 35 ng/mL during 30 days almost completely …”

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confidence: 99%

“…44,46 HUVECs or PMECs suspended in liquid Matrigel were subsequently injected subcutaneously, as detailed in previous work. 44 Briefly, endothelial cells (3 ϫ 10 5 ) suspended in 200 L Matrigel were injected in the midline of the abdomen, carefully positioning the needle between the epidermis and the muscle layer. The liquid Matrigel stiffens at body temperature to form a solid plug.…”

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confidence: 99%

Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo

Skovseth

Veuger

Sørensen

et al. 2005

Blood

Self Cite

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IntroductionThe formation of new capillaries from pre-existing vessels (angiogenesis) appears to be essential for tumor growth and survival. [1][2][3][4][5][6] Whereas hypoxic conditions in expanding tumors often initiate a cascade of endothelial cell sprouting and formation of new vessels, tumor growth can be arrested by inadequate blood supply and a lack of metabolic exchange, often leading to tumor necrosis and regression. 7 Several tumor-derived, circulating angiogenesis inhibitors generated in vivo by proteolytic degradation have been recently identified (reviewed in Cao 8 and Marneros and Olsen 9 ). In particular, a 20-kDa C-terminal proteolytic fragment of collagen XVIII, termed endostatin, inhibits tumor growth in several animal models. [10][11][12][13][14][15] Although the mechanisms of action are incompletely understood, endostatin reportedly interacts with several endothelial cell-surface receptors that are critically involved in angiogenesis. Endostatin binds directly to the fibronectin receptor ␣ 5 ␤ 1 16,17 and also interacts with ␣ v ␤ 3 and ␣ v ␤ 5 integrins. 17 In keeping with these interactions, endostatin inhibits endothelial cell binding to the ␣ v ␤ 3 -ligand gelatin 17 and also their binding to collagen type I in a dose-dependent manner. 18 Moreover, endostatin binds to heparan sulfate, [19][20][21][22] tropomyosin, 23 caveolin-1, 16 VEGFR-1 (vascular endothelial growth factor receptor-1; Flt-1), and VEGFR-2 (Flk-1) 24 and was recently shown to depend on E-selectin expression to be effective in vivo. 25 Interaction of endostatin with endothelial cells leads to a variety of downstream effects, [26][27][28] including inhibition of the Wnt/␤-catenin pathway, 29 and actin reorganization in endothelial cells. 16,[30][31][32][33] In fact, this wide variety of effects elicited by 1 endogenous inhibitor of angiogenesis was recently supported by 2 studies of global gene expression in endostatin-treated endothelial cells. 27,34 There is general agreement that the in vitro action of endostatin involves inhibition of endothelial cell migration, but less clear whether endostatin also affects endothelial cell apoptosis and proliferation. 6,12,26,[35][36][37][38][39] Furthermore, even less is known about how endostatin affects endothelial cell function in vivo, as readouts have been restricted to analysis of vascular density or blood flow in tumors, [12][13][14]35,40 or neovascularization of the chick allantoic membrane. 10,12,39 Moreover, studies that focused in more detail on endothelial cell behavior in vivo either failed to detect substantial effects of endostatin 41 or found subtle signs of impaired blood vessel maturation. 42 Finally, several studies failed to observe an antitumor effect of endostatin (reviewed in Marshall 43 ). Thus, there is an obvious need to more carefully analyze the effect of endostatin at the level of single endothelial cells during angiogenesis.Here, we describe the effect of endostatin in an in vivo model of human endothelial cell behavior in which the final stages of angio...

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Vascular Morphogenesis and Differentiation after Adoptive Transfer of Human Endothelial Cells to Immunodeficient Mice

Abstract: To establish a model for adoptive transfer of endothelial cells, we transferred human umbilical vein endothelial cells (HUVECs) to immunodeficient mice (Rag

Cited by 30 publications

References 40 publications

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

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

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

Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo

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