title: Circulating angiogenesis biomarkers are associated with disease progression in lung adenocarcinoma.
abstract: BACKGROUND
  Dysregulation of angiogenesis is known to be associated with tumorigenesis and metastatic progression in multiple carcinomas. The aim of this study was to evaluate the prognostic value of circulating angiogenesis biomarkers in lung adenocarcinoma progression. For that, we hypothesize that circulating levels of biomarkers characteristic for discrete processes within angiogenesis are associated with specific phases of disease progression. Appreciation of these profiles may have important implications for disease detection and prognostication.
  
  
  METHODS
  Patients with lung adenocarcinoma enrolled in the study were grouped as follows: node negative (T1a-3N0M0; n = 69), node positive (T1a-4N1-2M0; n = 60), and disseminated disease (TxNxM1; n = 68). All serum specimens were assayed for 17 angiogenesis biomarkers on the Luminex platform and statistically evaluated by analysis of variance for median differences in biomarker concentration at distinct phases of disease progression and by log rank methods for associations with clinical outcome.
  
  
  RESULTS
  We found circulating hepatocyte growth factor, heparin-binding epidermal growth factor, epidermal growth factor, and vascular endothelial growth factor-C levels significantly elevated (p < 0.05) in patients with node positive versus node negative disease. Similarly, median serum concentrations of bone morphogenic protein-9, endoglin, fibroblast growth factor-1, fibroblast growth factor-2, interleukin-8, placental growth factor, vascular endothelial growth factor-C, and vascular endothelial growth factor-D were significantly (p < 0.05) higher in patients with disseminated disease than in patients with node positive disease. Five biomarkers total were strongly prognostic (p < 0.05) for overall survival in the node negative cohort.
  
  
  CONCLUSIONS
  Angiogenesis is a process central to lung adenocarcinoma progression. We describe the modulation in serum angiogenesis biomarker concentrations through the various phases of non-small cell lung cancer progression. Additional refinement efforts are under way to enhance test performance, followed by additional validation studies.
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
authors.forename: Shaun
authors.initials: S
authors.lastname: Daly
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
authors.forename: John C
authors.initials: JC
authors.lastname: Kubasiak
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rinewalt
authors.affiliation: Department of Pathology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Ravi
authors.initials: R
authors.lastname: Pithadia
authors.affiliation: Department of Medical Oncology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Basu
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fhied
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.
authors.forename: Gabriela C
authors.initials: GC
authors.lastname: Lobato
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Seder
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
authors.forename: Edward
authors.initials: E
authors.lastname: Hong
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
authors.forename: William H
authors.initials: WH
authors.lastname: Warren
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
authors.forename: Gary
authors.initials: G
authors.lastname: Chmielewski
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Liptay
authors.affiliation: Department of Medical Oncology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Philip
authors.initials: P
authors.lastname: Bonomi
authors.affiliation: Department of Pathology, Rush University Medical Center, Chicago, Illinois; Department of Biochemistry, Rush University Medical Center, Chicago, Illinois. Electronic address: jeffrey_borgia@rush.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Borgia
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000150:complications; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000150:complications; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood* / Q000209:etiology; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor