title: Immunohistochemical analysis of phosphotyrosine signal transducer and activator of transcription 3 and epidermal growth factor receptor autocrine signaling pathways in head and neck cancers and metastatic lymph nodes.
abstract: OBJECTIVE
  To determine the effect of tyrosine-phosphorylated signal transducer and activator of transcription 3 (pSTAT3) immunoexpression on survival in two independent cohorts of patients with squamous cell carcinoma of the head and neck (SCCHN) and to evaluate pSTAT3, transforming growth factor-alpha (TGF-alpha), epidermal growth factor receptor (EGFR), and gastrin-releasing peptide receptor (GRPR) expression in matched tumor and lymph node metastases in one of these cohorts. EXPERIMENTAL TECHNIQUE: Immunostaining for pSTAT3, TGF-alpha, EGFR, and GRPR was done in two SCCHN cohorts (cohort 1, 61 tumors; cohort 2, 69 paired primary tumors and lymph node metastases). Semiquantitative scores derived from the product of staining intensity (scale 0-3) score and percentage of positive tumor cells were correlated with clinical outcome.
  
  
  RESULTS
  Immunoexpression of pSTAT3 did not correlate with clinical outcome in either cohort (cohort 1, P = 0.914; cohort 2, P = 0.312). In cohort 2, TGF-alpha and EGFR expression in the primary tumors showed some association with decreased disease-free survival (P = 0.0306 and P = 0.0985, respectively). Both pSTAT3 and EGFR showed a correlation of expression between tumor and matched lymph node metastasis (P < 0.0001 and P = 0.0046, respectively). In addition, the expression of EGFR and GRPR in the primary tumors correlated with TGF-alpha expression in paired nodal metastases (P = 0.0043 and P = 0.0268, respectively). In the nodal metastases, TGF-alpha expression correlated with EGFR expression (P = 0.0069). In primary tumors, GRPR expression correlated with TGF-alpha and EGFR expression (P = 0.0378 and P = 0.0026, respectively).
  
  
  CONCLUSIONS
  These findings support an autocrine signaling pathway involving TGF-alpha, EGFR, and pSTAT3 in metastatic SCCHN as well as transactivation of EGFR by GRPR via TGF-alpha, but fails to identify an independent prognostic role for pSTAT3 immunoexpression.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
authors.forename: Phoebe N
authors.initials: PN
authors.lastname: Handler
authors.forename: Bobby
authors.initials: B
authors.lastname: Collins
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jill M
authors.initials: JM
authors.lastname: Siegfried
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000556:secondary / Q000628:therapy; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D019000:Phosphotyrosine / Q000378:metabolism*; D018004:Receptors, Bombesin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D018004:Receptors, Bombesin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016211:Transforming Growth Factor alpha; D019000:Phosphotyrosine; D066246:ErbB Receptors