Endothelial CD34 is suppressed in human malignancies: role of angiogenic factors

Hellwig, Sandra M.M.; Damen, Cora A.; Adrichem, Niek P.H van; Blijham, Geert H.; Groenewegen, Gerard; Griffioen, Arjan W.

doi:10.1016/s0304-3835(97)00310-8

Cited by 56 publications

(42 citation statements)

References 19 publications

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“…Thus, the angiogenic stimulation of endothelium in ductal carcinoma suppresses the expression of adhesion molecules leading to the prevention of leukocyte infiltration. It is known that leukocyte infiltration can positively influence the prognosis of cancer (1,14), and the present results may therefore serve as an explanation for the better prognosis of medullary over ductal carcinoma.…”

Section: Discussionsupporting

confidence: 58%

“…The demonstration that endothelial expression of ICAM-1, which is the most important adhesion molecule for leukocyte extravasation [both necessary and sufficient (9)], is lower in ductal carcinoma suggests that the absence of adhesion molecules on the tumor vessels is the possible reason for the low level of infiltration as compared with medullary carcinoma. In previous studies, we have extensively demonstrated in in vitro and in vivo models that the process of tumor angiogenesis down-regulates leukocyte vessel wall interactions by suppression of endothelial adhesion molecules, such as ICAM-1, vascular cell adhesion molecule-1, E-selectin, and CD34 (14,16,17). Moreover, tumor endothelial cells were shown to be relatively unresponsive to proinflammatory cytokines, a process that we have called endothelial cell anergy, which is mediated through different mechanisms (5,18).…”

Section: Discussionmentioning

confidence: 99%

“…Slides were counterstained with hematoxylin (Merck) and mounted in entellan (Merck). Microvessel density was assessed as previously described (14), and leukocyte infiltration was determined by two independent observers in four randomly selected high-power fields (ϫ200). Results are expressed as number of vessels/mm 2 (CD31) or leukocytes/mm 2 .…”

Section: Preparation Of Single Cell Suspensions and Fluorescence-actimentioning

confidence: 99%

See 2 more Smart Citations

Angiogenic Profile of Breast Carcinoma Determines Leukocyte Infiltration

Steege¹,

Baeten²,

Thijssen³

et al. 2004

Clinical Cancer Research

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Preparation Of Single Cell Suspensions and Fluorescence-actimentioning

confidence: 99%

See 1 more Smart Citation

Angiogenic Profile of Breast Carcinoma Determines Leukocyte Infiltration

Steege¹,

Baeten²,

Thijssen³

et al. 2004

Clinical Cancer Research

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show abstract

“…Interference in the expression of endothelial cell adhesion molecules is one of the mechanisms tumors have developed to escape the immune response. We and others have shown previously that by producing angiogenic factors, such as vascular endothelial cell growth factors (VEGF) and basic fibroblast growth factors (FGF), tumors down-regulate vascular adhesion molecule expression (3)(4)(5)(6). This angiogenesis-mediated endothelial cell anergy to inflammatory signals results in diminished leukocytevessel wall interactions and, therefore, decreased inflammatory infiltration (7,8).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Hellebrekers

Castermans

Viré³

et al. 2006

Cancer Research

139

107

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Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocytevessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2 ¶-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro , resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys 4 methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be

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“…CD31 has also shown to be a sensitive marker in the endothelial cells (EC) (39). Among these markers, it has been reported that CD34 expression may be decreased by a potent angiogenic factor, the vascular endothelial growth factor (VEGF) (40). We thus used CD31 expression in the current study.…”

Section: Effects Of Ifn Rib and Arb On Hepatic Neovascularizationmentioning

confidence: 99%

Cocktail therapy with a combination of interferon, ribavirin and angiotensin-II type 1 receptor blocker attenuates murine liver fibrosis development

Yoshiji

Noguchi²,

Ikenaka³

et al. 2011

Int J Mol Med

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Abstract. An effective therapeutic strategy for suppressing liver fibrosis development should improve the overall prognosis of patients with chronic liver diseases. Despite efforts to develop anti-fibrotic agents, no drugs have yet been approved as anti-fibrotic treatments for humans. An alternative strategy may be to employ a clinically available agent that also exhibits anti-fibrotic activities, for which the safety of long-term administration has been proven. The aim of the current study was to elucidate the combined effect of clinically used interferon (IFN), ribavirin (Rib) and angiotensin-II receptor blocker (ARB) on liver fibrosis development in mice. A model of ccl 4 -induced hepatic fibrosis was used to assess the effect of IFN, Rib and ARB. IFN, Rib and ARB were administered after a two-week treatment with CCl 4 , and the hepatic indices of fibrosis were assessed at eight weeks. Single treatment with IFN, Rib or ARB at the clinically available comparable doses significantly attenuated the liver fibrogenesis associated with the suppression of the number of α-smooth muscle actin positive cells, and the hepatic transforming growth factor-β (TGF-β) mRNA. Hepatic neovascularization, which is also known to play a pivotal role in liver fibrogenesis, and vascular endothelial growth factor (VEGF), a potent angiogenic factor, were also markedly inhibited. Combination treatment with any two agents exerted a more potent inhibitory effect than any single treatment. Moreover, the triple cocktail treatment revealed further suppressive effects than any two agent combination. Furthermore, in vitro studies showed that similar combined effects were observed on the proliferation and TGF-β mRNA expression of activated hepatic stellate cells and endothelial cell tube formation. These results indicate that the cocktail combination treatment of clinically used IFN, Rib and ARB may provide a new strategy for anti-liver fibrosis therapy.

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Endothelial CD34 is suppressed in human malignancies: role of angiogenic factors

Cited by 56 publications

References 19 publications

Angiogenic Profile of Breast Carcinoma Determines Leukocyte Infiltration

Angiogenic Profile of Breast Carcinoma Determines Leukocyte Infiltration

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Cocktail therapy with a combination of interferon, ribavirin and angiotensin-II type 1 receptor blocker attenuates murine liver fibrosis development

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