Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer

Am, Jubb; Turley, Helen; Hc, Moeller; Steers, Graham; Han, Chen; Li, JL; Leek, Russell; Tan, Elaine; Singh, Baldev; Nj, Mortensen; Noguera-Troise, Irene; Pezzella, Francesco; Kc, Gatter; Thurston, Gavin; Fox, Stephen B.; Harris, Adrian L.

doi:10.1038/sj.bjc.6605368

Cited by 94 publications

(82 citation statements)

References 55 publications

(80 reference statements)

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“…43 Normal kidney did not express Dll4, but endothelial cells in renal cell carcinoma showed endothelial expression of Dll4, consistent with previous in situ hybridization results. 43,45,46 CA9 and CD31 were expressed in tumor cells adjacent to areas of necrosis and the endothelium of the control renal cell carcinoma tissue, respectively. 47,48 CD68 and CD14 were expressed predominantly by macrophages present within the germinal centers of control tonsil tissue.…”

Section: Frequency and Pattern Of Expressionsupporting

confidence: 90%

“…Slides were then dehydrated through a gradient of alcohols, air-dried, and immersed in liquid film emulsion (GE Health care, Chalfont St Giles, UK) for 14 days, before they were developed and counterstained with H&E. In situ hybridization for ␤-actin on a serial section was used as a positive control for mRNA integrity. 42 and Dll4 (clone 242; Regeneron, Tarrytown, NY) 43 was performed either manually or by using a Bond Max immunostaining machine (Leica) as per the manufacturer's instructions with controls for all experiments (tonsil and/or placenta for inflammatory cell markers; renal cell carcinoma for CA9 and CD31; and renal cell carcinoma, normal kidney, FFPE human umbilical vein endothelial cell pellets, and FFPE U87 cell pellets transfected with empty vector or recombinant human Dll4 43 for Dll4). Immunohistochemistry for Dll4 was performed by using an anti-Dll4 monoclonal antibody (the variable regions of this antibody are fully human, and the Fc-domain is mouse; clone 242) that binds to the extracellular domain of human Dll4 (the epitope is in epidermal growth factor-like domains 3 to 5) and generated in VelocImmune mice (Regeneron).…”

Section: Patients and Tissue Samplesmentioning

confidence: 99%

“…30 Although not specifically scored, 20% to 60% of tumor cells in approximately 5% of breast adenocarcinomas showed weak cytoplasmic/membranous expression of Dll4 (data not shown), consistent with results in colon cancer. 43,52 Immunohistochemistry for inflammatory cell markers selectively stained inflammatory cells with appropriate morphology. Cells positive for CD68, a panmyeloid marker, …”

Section: Frequency and Pattern Of Expressionmentioning

confidence: 99%

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Expression of Vascular Notch Ligand Delta-Like 4 and Inflammatory Markers in Breast Cancer

Jubb

Soilleux

Turley

et al. 2010

The American Journal of Pathology

102

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Delta-like ligand 4 (Dll4) is a Notch ligand that is predominantly expressed in the endothelium. Evidence from xenografts suggests that inhibiting Dll4 may overcome resistance to antivascular endothelial growth factor therapy. The aims of this study were to characterize the expression of Dll4 in breast cancer and assess whether it is associated with inflammatory markers and prognosis. We examined 296 breast adenocarcinomas and 38 ductal carcinoma in situ tissues that were represented in tissue microarrays. Additional whole sections representing 10 breast adenocarcinomas, 10 normal breast tissues, and 16 angiosarcomas were included. Immunohistochemistry was then performed by using validated antibodies against Dll4, CD68, CD14, Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), CD123, neutrophil elastase, CD31, and carbonic anhydrase 9. Dll4 was selectively expressed by intratumoral endothelial cells in 73% to 100% of breast adenocarcinomas, 18% of in situ ductal carcinomas, and all lactating breast cases, but not normal nonlactating breast. High intensity of endothelial Dll4 expression was a statistically significant adverse prognostic factor in univariate (P ‫؍‬ 0.002 and P ‫؍‬ 0.01) and multivariate analyses (P ‫؍‬ 0.03 and P ‫؍‬ 0.04) of overall survival and relapse-free survival, respectively. Among the inflammatory markers, only CD68 and DC-SIGN were significant prognostic factors in univariate (but not multivariate) analyses of overall survival (P ‫؍‬ 0.01 and 0.002, respectively). In summary, Dll4 was expressed by endothelium associated with breast cancer cells. In these retrospective subset analyses, endothelial Dll4 expression was a statistically significant multivariate prognostic factor. (Am J Pathol

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Section: Frequency and Pattern Of Expressionsupporting

confidence: 90%

Section: Patients and Tissue Samplesmentioning

confidence: 99%

Section: Frequency and Pattern Of Expressionmentioning

confidence: 99%

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Expression of Vascular Notch Ligand Delta-Like 4 and Inflammatory Markers in Breast Cancer

Jubb

Soilleux

Turley

et al. 2010

The American Journal of Pathology

102

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“…Renal cell carcinomas dramatically upregulate DLL4 specifically in the vasculature, as shown by in situ hybridization, and the expression is correlated to the abundance of VEGF (Patel et al, 2005). The expression of endothelial DLL4 and VEGF-A is also correlated in colon carcinoma (Jubb et al, 2009). Our studies indicate that repeated DNA vaccination against DLL4 holds therapeutic efficacy in two different orthotopic mouse models of ERBB2-expressing mammary carcinoma.…”

Section: Inhibition Of Tumor Growth Is Mediated By a Humoral Responsementioning

confidence: 51%

“…Little is known about the localization of DLL4 in human tissues. However, DLL4 is selectively expressed by the endothelium of malignant tissues, but not the normal counterparts in breast and colon (Jubb et al, 2009(Jubb et al, , 2010.…”

Section: Introductionmentioning

confidence: 95%

Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma

et al. 2010

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The Notch ligand delta-like ligand 4 (DLL4) is an essential component expressed by endothelial tip cells during angiogenic sprouting. We have described a conceptually novel therapeutic strategy for targeting tumor angiogenesis and endothelial tip cells based on DNA vaccination against DLL4. Immunization with DLL4-encoding plasmid DNA by in vivo electroporation severely retarded the growth of orthotopically implanted mammary carcinomas in mice by induction of a nonproductive angiogenic response. Mechanistically, vaccination brought about a break in tolerance against the self-antigen, DLL4, as evidenced by the production of inhibitory and inherently therapeutic antibodies against mouse DLL4. Importantly, no evidence for a delayed wound healing response, or for toxicity associated with pharmacological blockade of DLL4 signaling, was noted in mice immunized with the DLL4 vaccine. We have thus developed a well-tolerated DNA vaccination strategy targeting the endothelial tip cells and the antigen DLL4 with proven therapeutic efficacy in mouse models of mammary carcinoma; a disease that has been reported to dramatically induce the expression of DLL4. Conceivably, induction of immunity toward principal mediators of pathological angiogenesis could provide protection against recurrent malignant disease in the adjuvant setting.

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Notch3 signalling promotes tumour growth in colorectal cancer

Serafin

Persano

Moserle

et al. 2011

The Journal of Pathology

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Increased Notch1 activity has been observed in intestinal tumours, partially accomplished by β-catenin-mediated up-regulation of the Notch ligand Jagged-1. Whether further mechanisms of Notch activation exist and other Notch receptors might be involved is unclear. Microarray data indicated that Notch3 transcript levels are significantly up-regulated in primary and metastatic CRC samples compared to normal mucosa. Moreover, Notch3 protein was expressed at strong/moderate levels by 19.7% of 158 CRC samples analysed, and at weak levels by 51.2% of the samples. Intrigued by these findings, we sought to investigate whether Notch3 modulates oncogenic features of CRC cells. By exploiting xenografts of CRC cells with different tumourigenic properties in mice, we found that the aggressive phenotype was associated with altered expression of components of the Notch pathway, including Notch3, Delta-like 4 (DLL4), and Jagged-1 ligands. Stimulation with immobilized recombinant DLL4 or transduction with DLL4-expressing vectors dramatically increased Notch3 expression in CRC cells, associated with accelerated tumour growth. Forced expression of an active form of Notch3 mirrored the effects of DLL4 stimulation and increased tumour formation. Conversely, attenuation of Notch3 levels by shRNA resulted in perturbation of the cell cycle followed by reduction in cell proliferation, clonogenic capacity, and inhibition of tumour growth. Altogether, these findings indicate that Notch3 can modulate the tumourigenic properties of CRC cells and contributes to sustained Notch activity in DLL4-expressing tumours.

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Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer

Cited by 94 publications

References 55 publications

Expression of Vascular Notch Ligand Delta-Like 4 and Inflammatory Markers in Breast Cancer

Expression of Vascular Notch Ligand Delta-Like 4 and Inflammatory Markers in Breast Cancer

Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma

Notch3 signalling promotes tumour growth in colorectal cancer

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