title: Profiling of Vascular Endothelial Growth Factor Receptor Heterogeneity Identifies Protein Expression-defined Subclasses of Human Non-small Cell Lung Carcinoma.
abstract: BACKGROUND
  the vascular endothelial growth factor (VEGF) pathway plays a prominent role in the growth and progression of human cancer, including non-small cell lung carcinoma (NSCLC). The key mediators of VEGF signaling are a family of related receptor tyrosine kinases that include VEGFR1, VEGFR2, and VEGFR3. The relative expression levels, activity, and cross-talk among these receptors may contribute to response of NSCLC to anti-angiogenic therapies, and a better systematic, translatable approach to categorizing tumors is needed.
  
  
  METHODS
  We comparatively evaluated immunohistochemical expression of the three VEGFRs in archival primary NSCLC tissues (n=96).
  
  
  RESULTS
  VEGFR1 and VEGFR2 were localized both in vessels and tumor cells, while VEGFR3 was only localized in tumor vessels. A set of eight VEGFR staining subclasses were identified: Triple VEGFR positive (n=11, 11.5%), VEGFR1 predominant (n=22, 22.9%), VEGFR2 predominant (n=9, 9.4%), VEGFR3 predominant (n=3, 3.1%), VEGFR1/2 predominant (13, 13.5%), VEGFR1/3 predominant (2, 2.1%), VEGFR2/3 predominant (n=8, 8.3%), and triple VEGFR negative (n=28, 29.2%). An objective categorization based on K-means clustering revealed four clusters, three of which showed high VEGFR2 compared to VEGFR3 (30.7% of cases), cases high in both VEGFR2 and VEGFR3 (18.2%), and cases that were negative/low for both VEGFR2 and VEGFR3 (45.4%). A positive association between VEGFR2 and VEGFR3 was found, however no associations were observed between VEGFR1 and VEGFR2, nor VEGFR1 and VEGFR3.
  
  
  CONCLUSIONS
  The proposed subclasses of NSCLC are an approach for complementing lines of investigation of anti-angiogenic therapies beginning with systematic characterization of the disease.
authors.affiliation: Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A. holzertr@lilly.com nasirae@lilly.com.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Holzer
authors.affiliation: Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
authors.forename: Angie D
authors.initials: AD
authors.lastname: Fulford
authors.affiliation: Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
authors.forename: Leslie O'Neill
authors.initials: LO
authors.lastname: Reising
authors.affiliation: Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Nedderman
authors.affiliation: Oncology Statistics, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
authors.forename: Xuekui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cancer Biology and Angiogenesis, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
authors.affiliation: Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Schade
authors.affiliation: Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A. holzertr@lilly.com nasirae@lilly.com.
authors.forename: Aejaz
authors.initials: A
authors.lastname: Nasir
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000145:classification* / Q000201:enzymology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000145:classification* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis
chemical_list: C501162:FLT1 protein, human; C581309:FLT4 protein, human; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: NSCLC; VEGFR; VEGFR1; VEGFR2; VEGFR3; immunohistochemistry; lung cancer; non-small cell lung cancer