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• W2014016903 endingPage "2028" @default.
• W2014016903 startingPage "2019" @default.
• W2014016903 abstract "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. 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. The growth of tumors requires angiogenesis,1Borgstrom P Gold DP Hillan KJ Ferrara N Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin.Anticancer Res. 1999; 19: 4203-4214PubMed Google Scholar which is the consequence of increased expression of proangiogenic factors (for example, vascular endothelial growth factor A [VEGF]2Kim KJ Li B Winer J Armanini M Gillett N Phillips HS Ferrara N Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.Nature. 1993; 362: 841-844Crossref PubMed Scopus (3342) Google Scholar, 3Viacava P Naccarato AG Bocci G Fanelli G Aretini P Lonobile A Evangelista G Montruccoli G Bevilacqua G Angiogenesis and VEGF expression in pre-invasive lesions of the human breast.J Pathol. 2004; 204: 140-146Crossref PubMed Scopus (59) Google Scholar). The expression of VEGF in cancer is controlled by oncogenic signaling,4Petit AM Rak J Hung MC Rockwell P Goldstein N Fendly B Kerbel RS Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors.Am J Pathol. 1997; 151: 1523-1530PubMed Google Scholar hypoxia,5Blancher C Moore JW Talks KL Houlbrook S Harris AL Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines.Cancer Res. 2000; 60: 7106-7113PubMed Google Scholar and inflammatory cells.6Lin EY Li JF Gnatovskiy L Deng Y Zhu L Grzesik DA Qian H Xue XN Pollard JW Macrophages regulate the angiogenic switch in a mouse model of breast cancer.Cancer Res. 2006; 66: 11238-11246Crossref PubMed Scopus (810) Google Scholar Although there is redundancy among proangiogenic factors in advanced cancer,7Relf M LeJeune S Scott PA Fox S Smith K Leek R Moghaddam A Whitehouse R Bicknell R Harris AL Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis.Cancer Res. 1997; 57: 963-969PubMed Google Scholar many in vivo early stage cancer models show VEGF dependence.8Hanrahan V Currie M Gunningham S Morrin H Scott P Robinson B Fox S The angiogenic switch for vascular endothelial growth factor (VEGF)-A. VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression.J Pathol. 2003; 200: 183-194Crossref PubMed Scopus (196) Google Scholar, 9Joyce JA Laakkonen P Bernasconi M Bergers G Ruoslahti E Hanahan D Stage-specific vascular markers revealed by phage display in a mouse model of pancreatic islet tumorigenesis.Cancer Cell. 2003; 4: 393-403Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar This observation has been exploited clinically, where the addition of an anti-VEGF antibody (bevacizumab) to first line taxane-based chemotherapy in recurrent/metastatic breast cancer was associated with prolongation of progression free survival (from a median of 5.9 to 11.8 months, P < 0.001).10Miller K Wang M Gralow J Dickler M Cobleigh M Perez EA Shenkier T Cella D Davidson NE Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.N Engl J Med. 2007; 357: 2666-2676Crossref PubMed Scopus (2708) Google Scholar Nevertheless, there was no statistically significant overall survival benefit, and all patients in this trial eventually progressed after 4 years.10Miller K Wang M Gralow J Dickler M Cobleigh M Perez EA Shenkier T Cella D Davidson NE Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.N Engl J Med. 2007; 357: 2666-2676Crossref PubMed Scopus (2708) Google Scholar Furthermore, a trial evaluating the addition of bevacizumab to capecitabine in previously treated metastatic/advanced breast cancer demonstrated only a 10.7% improvement in response rate and no survival benefit.11Miller KD Chap LI Holmes FA Cobleigh MA Marcom PK Fehrenbacher L Dickler M Overmoyer BA Reimann JD Sing AP Langmuir V Rugo HS Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.J Clin Oncol. 2005; 23: 792-799Crossref PubMed Scopus (1223) Google Scholar To date, there are no validated clinical, radiological, or molecular biomarkers that can predict the survival benefit afforded by bevacizumab.12Grothey A Hedrick EE Mass RD Sarkar S Suzuki S Ramanathan RK Hurwitz HI Goldberg RM Sargent DJ Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107.J Clin Oncol. 2008; 26: 183-189Crossref PubMed Scopus (148) Google Scholar, 13Grothey A Sugrue MM Purdie DM Dong W Sargent D Hedrick E Kozloff M Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE).J Clin Oncol. 2008; 26: 5326-5334Crossref PubMed Scopus (628) Google Scholar, 14Ince WL Jubb AM Holden SN Holmgren EB Tobin P Sridhar M Hurwitz HI Kabbinavar F Novotny WF Hillan KJ Koeppen H Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab.J Natl Cancer Inst. 2005; 97: 981-989Crossref PubMed Scopus (299) Google Scholar, 15Jubb AM Hurwitz HI Bai W Holmgren EB Tobin P Guerrero AS Kabbinavar F Holden SN Novotny WF Frantz GD Hillan KJ Koeppen H Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer.J Clin Oncol. 2006; 24: 217-227Crossref PubMed Scopus (347) Google Scholar Clinical data suggest that antiangiogenic drugs are active in breast cancer,10Miller K Wang M Gralow J Dickler M Cobleigh M Perez EA Shenkier T Cella D Davidson NE Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.N Engl J Med. 2007; 357: 2666-2676Crossref PubMed Scopus (2708) Google Scholar, 16Wedam SB Low JA Yang SX Chow CK Choyke P Danforth D Hewitt SM Berman A Steinberg SM Liewehr DJ Plehn J Doshi A Thomasson D McCarthy N Koeppen H Sherman M Zujewski J Camphausen K Chen H Swain SM Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer.J Clin Oncol. 2006; 24: 769-777Crossref PubMed Scopus (479) Google Scholar and it may be necessary to identify biomarkers that predict their benefit. Additional agents that disrupt functional angiogenesis have been developed to target tumors resistant to anti-VEGF therapy.17Noguera-Troise I Daly C Papadopoulos NJ Coetzee S Boland P Gale NW Lin HC Yancopoulos GD Thurston G Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.Nature. 2006; 444: 1032-1037Crossref PubMed Scopus (874) Google Scholar, 18Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.Nature. 2006; 444: 1083-1087Crossref PubMed Scopus (823) Google Scholar Recent studies have focused on Delta-like ligand 4 (Dll4), a ligand for Notch receptors 1, 3, and 417Noguera-Troise I Daly C Papadopoulos NJ Coetzee S Boland P Gale NW Lin HC Yancopoulos GD Thurston G Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.Nature. 2006; 444: 1032-1037Crossref PubMed Scopus (874) Google Scholar, 18Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.Nature. 2006; 444: 1083-1087Crossref PubMed Scopus (823) Google Scholar, 19Indraccolo S Minuzzo S Masiero M Pusceddu I Persano L Moserle L Reboldi A Favaro E Mecarozzi M Di Mario G Screpanti I Ponzoni M Doglioni C Amadori A Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy.Cancer Res. 2009; 69: 1314-1323Crossref PubMed Scopus (111) Google Scholar that is predominantly expressed by endothelial cells.17Noguera-Troise I Daly C Papadopoulos NJ Coetzee S Boland P Gale NW Lin HC Yancopoulos GD Thurston G Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.Nature. 2006; 444: 1032-1037Crossref PubMed Scopus (874) Google Scholar, 18Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.Nature. 2006; 444: 1083-1087Crossref PubMed Scopus (823) Google Scholar, 19Indraccolo S Minuzzo S Masiero M Pusceddu I Persano L Moserle L Reboldi A Favaro E Mecarozzi M Di Mario G Screpanti I Ponzoni M Doglioni C Amadori A Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy.Cancer Res. 2009; 69: 1314-1323Crossref PubMed Scopus (111) Google Scholar Transgenic mice in which Dll4 was replaced by a reporter gene showed that Dll4 expression is restricted to large arteries during development.20Gale NW Dominguez MG Noguera I Pan L Hughes V Valenzuela DM Murphy AJ Adams NC Lin HC Holash J Thurston G Yancopoulos GD Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.Proc Natl Acad Sci USA. 2004; 101: 15949-15954Crossref PubMed Scopus (494) Google Scholar, 21Sainson RC Harris AL Regulation of angiogenesis by homotypic and heterotypic notch signalling in endothelial cells and pericytes: from basic research to potential therapies.Angiogenesis. 2008; 11: 41-51Crossref PubMed Scopus (77) Google Scholar Furthermore, Dll4 heterozygous knockout mice are reported to have defective arterial development22Duarte A Hirashima M Benedito R Trindade A Diniz P Bekman E Costa L Henrique D Rossant J Dosage-sensitive requirement for mouse Dll4 in artery development.Genes Dev. 2004; 18: 2474-2478Crossref PubMed Scopus (452) Google Scholar and venous malformations.22Duarte A Hirashima M Benedito R Trindade A Diniz P Bekman E Costa L Henrique D Rossant J Dosage-sensitive requirement for mouse Dll4 in artery development.Genes Dev. 2004; 18: 2474-2478Crossref PubMed Scopus (452) Google Scholar Experimental systems17Noguera-Troise I Daly C Papadopoulos NJ Coetzee S Boland P Gale NW Lin HC Yancopoulos GD Thurston G Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.Nature. 2006; 444: 1032-1037Crossref PubMed Scopus (874) Google Scholar, 23Hellstrom M Phng LK Hofmann JJ Wallgard E Coultas L Lindblom P Alva J Nilsson AK Karlsson L Gaiano N Yoon K Rossant J Iruela-Arispe ML Kalen M Gerhardt H Betsholtz C Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.Nature. 2007; 445: 776-780Crossref PubMed Scopus (1300) Google Scholar, 24Siekmann AF Lawson ND Notch signalling limits angiogenic cell behavior in developing zebrafish arteries.Nature. 2007; 445: 781-784Crossref PubMed Scopus (533) Google Scholar have shown that Dll4-Notch inhibition leads to increased sprouting and branching of vessels in association with gradients of VEGF. Conversely, VEGF blockade causes a reduction in Dll4 expression and vessel sprouting.17Noguera-Troise I Daly C Papadopoulos NJ Coetzee S Boland P Gale NW Lin HC Yancopoulos GD Thurston G Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.Nature. 2006; 444: 1032-1037Crossref PubMed Scopus (874) Google Scholar, 18Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.Nature. 2006; 444: 1083-1087Crossref PubMed Scopus (823) Google Scholar, 23Hellstrom M Phng LK Hofmann JJ Wallgard E Coultas L Lindblom P Alva J Nilsson AK Karlsson L Gaiano N Yoon K Rossant J Iruela-Arispe ML Kalen M Gerhardt H Betsholtz C Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.Nature. 2007; 445: 776-780Crossref PubMed Scopus (1300) Google Scholar, 24Siekmann AF Lawson ND Notch signalling limits angiogenic cell behavior in developing zebrafish arteries.Nature. 2007; 445: 781-784Crossref PubMed Scopus (533) Google Scholar, 25Suchting S Freitas C le Noble F Benedito R Breant C Duarte A Eichmann A The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.Proc Natl Acad Sci USA. 2007; 104: 3225-3230Crossref PubMed Scopus (622) Google Scholar, 26Lobov IB Renard RA Papadopoulos N Gale NW Thurston G Yancopoulos GD Wiegand SJ Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting.Proc Natl Acad Sci USA. 2007; 104: 3219-3224Crossref PubMed Scopus (591) Google Scholar, 27Leslie JD Ariza-McNaughton L Bermange AL McAdow R Johnson SL Lewis J Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis.Development. 2007; 134: 839-844Crossref PubMed Scopus (335) Google Scholar In addition, endothelial cells transfected with Dll4 down-regulated VEGF receptors KDR and neuropilin1 and showed reduced proliferative and migratory responses to VEGF.28Williams CK Li JL Murga M Harris AL Tosato G Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function.Blood. 2006; 107: 931-939Crossref PubMed Scopus (304) Google Scholar The implication of this research is that Dll4-Notch signaling regulates endothelial sprouting and branching to form functional vascular beds, under the control of VEGF and by autoregulation of VEGF signaling.23Hellstrom M Phng LK Hofmann JJ Wallgard E Coultas L Lindblom P Alva J Nilsson AK Karlsson L Gaiano N Yoon K Rossant J Iruela-Arispe ML Kalen M Gerhardt H Betsholtz C Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.Nature. 2007; 445: 776-780Crossref PubMed Scopus (1300) Google Scholar Disruption of Dll4 signaling by overexpression or inhibition of Dll4 may impair angiogenesis,17Noguera-Troise I Daly C Papadopoulos NJ Coetzee S Boland P Gale NW Lin HC Yancopoulos GD Thurston G Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.Nature. 2006; 444: 1032-1037Crossref PubMed Scopus (874) Google Scholar, 18Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.Nature. 2006; 444: 1083-1087Crossref PubMed Scopus (823) Google Scholar and blockade of Dll4-Notch signaling results in an increased density of nonfunctional vasculature and is associated with a reduction in the growth of human tumor xenografts.17Noguera-Troise I Daly C Papadopoulos NJ Coetzee S Boland P Gale NW Lin HC Yancopoulos GD Thurston G Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.Nature. 2006; 444: 1032-1037Crossref PubMed Scopus (874) Google Scholar, 18Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.Nature. 2006; 444: 1083-1087Crossref PubMed Scopus (823) Google Scholar Indeed, certain xenografts that are resistant to anti-VEGF therapy are reported to be sensitive to anti-Dll4,17Noguera-Troise I Daly C Papadopoulos NJ Coetzee S Boland P Gale NW Lin HC Yancopoulos GD Thurston G Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.Nature. 2006; 444: 1032-1037Crossref PubMed Scopus (874) Google Scholar, 18Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.Nature. 2006; 444: 1083-1087Crossref PubMed Scopus (823) Google Scholar, 29Li JL Sainson RC Shi W Leek R Harrington LS Preusser M Biswas S Turley H Heikamp E Hainfellner JA Harris AL Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo.Cancer Res. 2007; 67: 11244-11253Crossref PubMed Scopus (267) Google Scholar and combination treatment with anti-VEGF and anti-Dll4 has additive inhibitory effects on tumor growth.18Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.Nature. 2006; 444: 1083-1087Crossref PubMed Scopus (823) Google Scholar Together these data provide a rationale to target Dll4 in cancer and suggest that Dll4 may have a role in mediating resistance to anti-VEGF therapies. Besides direct vascular effects, Fung et al30Fung E Tang SM Canner JP Morishige K Arboleda-Velasquez JF Cardoso AA Carlesso N Aster JC Aikawa M Delta-like 4 induces notch signaling in macrophages: implications for inflammation.Circulation. 2007; 115: 2948-2956Crossref PubMed Scopus (179) Google Scholar showed that Dll4-Notch signaling in macrophages stimulates a proinflammatory response, which may be proangiogenic.6Lin EY Li JF Gnatovskiy L Deng Y Zhu L Grzesik DA Qian H Xue XN Pollard JW Macrophages regulate the angiogenic switch in a mouse model of breast cancer.Cancer Res. 2006; 66: 11238-11246Crossref PubMed Scopus (810) Google Scholar Moreover, Shojaei et al31Shojaei F Wu X Malik AK Zhong C Baldwin ME Schanz S Fuh G Gerber HP Ferrara N Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells.Nature Biotechnol. 2007; 25: 911-920Crossref Scopus (709) Google Scholar, 32Shojaei F Wu X Qu X Kowanetz M Yu L Tan M Meng YG Ferrara N G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models.Proc Natl Acad Sci USA. 2009; 106: 6742-6747Crossref PubMed Scopus (391) Google Scholar have reported that bevacizumab resistance in certain preclinical in vivo cancer models is causally associated with tumor infiltration by myeloid cells. The characterization of Dll4 protein expression in human cancer is important for the rational design of clinical trials to test the safety and activity of anti-Dll4 therapy. Defining the pattern of Dll4 expression, in association with markers of inflammation, may identify subgroups with distinct clinical behavior and responses to treatment. The aims of this study were to characterize the in situ expression of Dll4 in breast cancer, to assess the association between Dll4 and established markers of inflammation (CD68, CD14, neutrophil elastase, CD123, and Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin [DC-SIGN]) and hypoxia (carbonic anhydrase 9 [CA9]), and to determine the prognostic significance of these markers. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained for 296 sequential patients with breast adenocarcinoma (surgery was performed between 1989 and 1998 at the John Radcliffe Hospital, Oxford, UK). Patients were treated with a wide local excision and postoperative radiotherapy or mastectomy with or without postoperative radiotherapy. Postoperative chemotherapy (600 mg/m2 cyclophosphamide, 40 mg/m2 methotrexate, and 600 mg/m2 5-fluorouracil intravenously each on day 1 of a 21-day cycle ×6) and hormonal therapy (tamoxifen 20 mg daily for 5 years) were offered according to local protocols. Demographic, pathological, and treatment details are provided in Supplemental Table S1 (see http://ajp.amjpathol.org). Sample size was determined by the availability of tissue with clinicopathological data, survival follow-up, and ethical approval for research. Two cases had no survival data available. Follow-up data were correct as of January 2008, with a median follow-up time of 10 years, a median overall survival of 13.7 years, and a median relapse-free survival of 13.8 years. Estrogen receptor (ER) content was determined by using an enzyme-linked immunosorbent assay technique (Abbott Laboratories, Abbott Park, IL). Tumors were considered positive when cytosolic ER levels were >10 fmol/mg of total cytosolic protein. Receptor values were monitored by participation in the European Organization for Research and Treatment of Cancer (EORTC) quality control scheme. Human Epidermal growth factor Receptor 2 (HER2) status was assessed with the HercepTest (Dako, Carpinteria, CA). Tissue microarrays (TMAs) were assembled as described previously33Bubendorf L Nocito A Moch H Sauter G Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies.J Pathol. 2001; 195: 72-79Crossref PubMed Scopus (325) Google Scholar with three replicate cores for each tumor. Tissue from 38 patients with breast ductal carcinoma in situ was also represented in TMAs for analysis. An additional 10 breast adenocarcinomas, five normal breast resections, five normal lactating breast tissues, seven breast angiosarcomas, and nine nonbreast angiosarcomas (five skin, one duodenal, one liver, one pleural, and one vaginal) were also collected (John Radcliffe Hospital) to investigate the expression of Dll4 in whole sections. Approval was obtained for the use of all human tissue from the local research ethics committee (C02.216). The National Cancer Institute’s Reporting Recommendations for Tumor Marker Prognostic Studies criteria were used in the design, analysis, and interpretation of this research.34McShane LM Altman DG Sauerbrei W Taube SE Gion M Clark GM Reporting recommendations for tumor marker prognostic studies (REMARK).J Natl Cancer Inst. 2005; 97: 1180-1184Crossref PubMed Scopus (1140) Google Scholar A 727 base 35S-labeled (35S-UTP 800 Ci/mmol; PerkinElmer, Waltham, MA) antisense riboprobe 100% homologous to human DLL4 (position 2089 to 2815 of GenBank accession NM_019074.2) was generated by using T3 RNA polymerase (Promega, Southampton, UK) from a linearized blunt ended vector containing the above insert. Isotopic in situ hybridization, washes, and developing were performed by using previously described methods.35Poulsom R Longcroft JM Jeffery RE Rogers LA Steel JH A robust method for isotopic riboprobe in situ hybridization to localize mRNAs in routine pathology specimens.Eur J Histochem. 1998; 42: 121-132PubMed Google Scholar In brief, FFPE tissue sections were deparaffinized in xylenes and rehydrated through graded alcohols. Deproteination was performed for 15 minutes at 37°C with 20 μg/ml proteinase K (Sigma-Aldrich, Gillingham, UK). Slides were air-dried before hybridization overnight at 55°C. Posthybridization, a series of increasingly stringent washes were performed, and unhybridized probe was digested with 20 mg/ml RNase A (Sigma-Aldrich) for 60 minutes at 37°C. 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 β-actin on a serial section was used as a positive control for mRNA integrity. Immunohistochemistry for CD68 (clone KP1; Nuffield Department of Clinical Laboratory Sciences, University of Oxford, UK),36Williams CS Leek RD Robson AM Banerji S Prevo R Harris AL Jackson DG Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer.J Pathol. 2003; 200: 195-206Crossref PubMed Scopus (181) Google Scholar CD14 (clone 223; Leica Microsystems, Newcastle-on-Tyne, UK),37Soilleux EJ Morris LS Leslie G Chehimi J Luo Q Levroney E Trowsdale J Montaner LJ Doms RW Weissman D Coleman N Lee B Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro.J Leukoc Biol. 2002; 71: 445-457PubMed Google Scholar neutrophil elastase (clone NP57; Nuffield Department of Clinical Laboratory Sciences),38Pulford KA Erber WN Crick JA Olsson I Micklem KJ Gatter KC Mason DY Use of monoclonal antibody against human neutrophil elastase in normal and leukaemic myeloid cells.J Clin Pathol. 1988; 41: 853-860Crossref PubMed Scopus (55) Google Scholar DC-SIGN (clone DC28; R and D Systems, Minneapolis, MN),39Soilleux EJ Sarno EN Hernandez MO Moseley E Horsley J Lopes UG Goddard MJ Vowler SL Coleman N Shattock RJ Sampaio EP DC-SIGN association with the Th2 environment of lepromatous lesions: cause or effect?.J Pathol. 2006; 209: 182-189Crossref PubMed Scopus (28) Google Scholar CD31 (clone JC/70a; Dako),36Williams CS Leek RD Robson AM Banerji S Prevo R Harris AL Jackson DG Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer.J Pathol. 2003; 200: 195-206Crossref PubMed Scopus (181) Google Scholar CA9 (clone M75; a gift from Professor S. Pastorekova and Professor J. Pastorek, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic),40Loncaster JA Harris AL Davidson SE Logue JP Hunter RD Wycoff CC Pastorek J Ratcliffe PJ Stratford IJ West CM Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix.Cancer Res. 2001; 61: 6394-6399PubMed Google Scholar, 41Pastorekova S Zavadova Z Kostal M Babusikova O Zavada J A novel quasi-viral agent. MaTu, is a two-component system.Virology. 1992; 187: 620-626Crossref PubMed Scopus (270) Google Scholar CD123 (clone 7G3; BD Pharmingen, San Diego, CA),42Sun Q Woodcock JM Rapoport A Stomski FC Korpelainen EI Bagley CJ Goodall GJ Smith WB Gamble JR Vadas MA Lopez AF Monoclonal antibody 7G3 recognizes the N-terminal domain of the human interleukin-3 (IL-3) receptor alpha-chain and fu" @default.
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• W2014016903 title "Expression of Vascular Notch Ligand Delta-Like 4 and Inflammatory Markers in Breast Cancer" @default.
• W2014016903 cites W1884314201 @default.
• W2014016903 cites W1962692964 @default.
• W2014016903 cites W1969328947 @default.
• W2014016903 cites W1971162717 @default.
• W2014016903 cites W1975044445 @default.
• W2014016903 cites W1987662957 @default.
• W2014016903 cites W1994550828 @default.
• W2014016903 cites W2002483118 @default.
• W2014016903 cites W2003635168 @default.
• W2014016903 cites W2020630926 @default.
• W2014016903 cites W2022236146 @default.
• W2014016903 cites W2024022674 @default.
• W2014016903 cites W2025708528 @default.
• W2014016903 cites W2028476709 @default.
• W2014016903 cites W2031191981 @default.
• W2014016903 cites W2040827891 @default.
• W2014016903 cites W2049299149 @default.
• W2014016903 cites W2051319925 @default.
• W2014016903 cites W2056296460 @default.
• W2014016903 cites W2056916102 @default.
• W2014016903 cites W2057796145 @default.
• W2014016903 cites W2058446569 @default.
• W2014016903 cites W2061368965 @default.
• W2014016903 cites W2062240872 @default.
• W2014016903 cites W2068915580 @default.
• W2014016903 cites W2073465941 @default.
• W2014016903 cites W2076274098 @default.
• W2014016903 cites W2079124802 @default.
• W2014016903 cites W2084293525 @default.
• W2014016903 cites W2085851286 @default.
• W2014016903 cites W2096910745 @default.
• W2014016903 cites W2101144899 @default.
• W2014016903 cites W2101711321 @default.
• W2014016903 cites W2104104624 @default.
• W2014016903 cites W2114159573 @default.
• W2014016903 cites W2117188579 @default.
• W2014016903 cites W2120009106 @default.
• W2014016903 cites W2123366765 @default.
• W2014016903 cites W2123634971 @default.
• W2014016903 cites W2126275851 @default.
• W2014016903 cites W2127690773 @default.
• W2014016903 cites W2128295200 @default.
• W2014016903 cites W2137358665 @default.
• W2014016903 cites W2139731402 @default.
• W2014016903 cites W2139877124 @default.
• W2014016903 cites W2145508988 @default.
• W2014016903 cites W2153726848 @default.
• W2014016903 cites W2157019123 @default.
• W2014016903 cites W2157930949 @default.
• W2014016903 cites W2160947862 @default.
• W2014016903 cites W2167133646 @default.
• W2014016903 cites W2282129010 @default.
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