title: Clinical implications of DLL4 expression in gastric cancer.
abstract: BACKGROUND
  Delta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor neovascular development and angiogenesis during tumor growth. The clinical significance of DLL4 expression in gastric cancer has not been clarified.
  
  
  METHODS
  Gastric cancer cell lines and 180 gastric cancer patients were enrolled. DLL4 expression in gastric cancer cells and stroma was identified and evaluated immunohistochemically. The association between DLL4 and clinicopathological factors was also assessed.
  
  
  RESULTS
  DLL4 expression was identified in the cellular membrane and cytoplasm of gastric cancer cells by immunoblotting and immunohistochemical staining. DLL4 positivity in cancer cells and stroma was found in 88 (48%) and 41 (22%) of the 180 gastric cancer patients respectively. Both cancer and stromal DLL4 expression significantly correlated with more advanced tumor depth, nodal involvement, and lymphatic and venous invasion. A strongly positive association between cancerous and stromal DLL4 expression was identified (p < 0.01). Both cancerous and stromal DLL4 expression were prognostic markers in gastric cancer as determined by univariate analysis.
  
  
  CONCLUSIONS
  Cancerous and stromal DLL4 expression was found in 48% and 22% in gastric cancer, and significantly affected postoperative clinical outcomes. Cancerous and stromal DLL4 expression may be an effective target of anti-DLL4 treatment in gastric cancer.
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan. suishigami@hotmail.com
authors.forename: Sumiya
authors.initials: S
authors.lastname: Ishigami
authors.forename: Takaaki
authors.initials: T
authors.lastname: Arigami
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uenosono
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okumura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurahara
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Uchikado
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Setoyama
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kijima
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nishizono
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakajo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Owaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ueno
authors.forename: Shoji
authors.initials: S
authors.lastname: Natsugoe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins
references.citation: Cancer Res. 2011 Sep 15;71(18):6073-83
references.pmid: 21803743
references.citation: Clin Cancer Res. 2006 Aug 15;12(16):4836-44
references.pmid: 16914569
references.citation: Cancer. 2010 Dec 15;116(24):5676-85
references.pmid: 20737536
references.citation: Scand J Surg. 2006;95(4):236-42
references.pmid: 17249271
references.citation: Int J Clin Oncol. 2003 Aug;8(4):200-6
references.pmid: 12955574
references.citation: Clin Cancer Res. 2011 Jan 15;17(2):372-81
references.pmid: 21224365
references.citation: Vasc Cell. 2011 Sep 18;3(1):20
references.pmid: 21923938
references.citation: Cell. 2009 Jun 12;137(6):1124-35
references.pmid: 19524514
references.citation: Clin Cancer Res. 2009 Apr 1;15(7):2291-301
references.pmid: 19258443
references.citation: Gastric Cancer. 1998 Dec;1(1):10-24
references.pmid: 11957040
references.citation: Oncologist. 2004;9 Suppl 1:11-8
references.pmid: 15178811
references.citation: J Cancer Res Ther. 2009 Oct-Dec;5(4):225-31
references.pmid: 20160354
references.citation: J Mammary Gland Biol Neoplasia. 2005 Oct;10(4):319-23
references.pmid: 16924373
references.citation: Lancet Oncol. 2005 May;6(5):266
references.pmid: 15889502
references.citation: Mol Cancer Ther. 2012 Aug;11(8):1650-60
references.pmid: 22679110
references.citation: Cancer Res. 2009 Jun 15;69(12):5039-48
references.pmid: 19491270
references.citation: J Clin Oncol. 2011 Mar 1;29(7):868-74
references.pmid: 21189380
references.citation: Differentiation. 2001 Dec;69(2-3):135-44
references.pmid: 11798067
references.citation: Nature. 2006 Dec 21;444(7122):1083-7
references.pmid: 17183323
references.citation: Oncogene. 2008 Sep 1;27(38):5132-7
references.pmid: 18758482
references.citation: Nature. 2006 Dec 21;444(7122):1032-7
references.pmid: 17183313
references.citation: N Engl J Med. 1971 Nov 18;285(21):1182-6
references.pmid: 4938153
references.citation: Cancer Res. 2007 Dec 1;67(23):11244-53
references.pmid: 18056450
references.citation: Br J Cancer. 2009 Nov 17;101(10):1749-57
references.pmid: 19844231
references.citation: Curr Treat Options Oncol. 2010 Jun;11(1-2):14-23
references.pmid: 20358316
references.citation: Curr Treat Options Oncol. 2005 Sep;6(5):411-21
references.pmid: 16107244
references.citation: Am J Pathol. 2010 Apr;176(4):2019-28
references.pmid: 20167860