title: Role of EGFR family receptors in proliferation of squamous carcinoma cells induced by wound healing fluids of head and neck cancer patients.
abstract: BACKGROUND
  Mounting evidence suggests that recurrence of resected head and neck squamous cell carcinomas (HNSCCs) is due to the outgrowth of unrecognized residual tumor cells as well as to the premalignant and/or precursor-field epithelial cells. We studied the impact of processes triggered by HNSCC surgery in stimulating both residual tumor cells [demonstrated to overexpress epidermal growth factor receptor (EGFR)], and premalignant cells surrounding the resected lesion.
  
  
  METHODS
  EGFR expression/activation by immunohistochemistry/biochemistry and gene status by FISH were investigated in 23 primary HNSCCs and surrounding tissues. The ability to induce cell proliferation of wound healing drainages collected from 12 relapsed and 11 not relapsed patients was evaluated by a colorimetric assay in squamous cell carcinoma cell lines A431 (carrying EGFR amplification) and CAL27 (carrying three EGFR copies) in the presence/absence of EGFR therapeutic inhibitors.
  
  
  RESULTS
  Primary tumors showed intermediate/high EGFR expression (91%), EGFR phosphorylation and EGFR-positive FISH (35%). Normal, metaplastic and dysplastic epithelium surrounding the resected tumor displayed EGFR overexpression. EGFR activation and gene amplification were observed in normal and dysplastic epithelium, respectively. Each tested wound healing drainage induced the cells to proliferate and the proliferation was significantly higher in relapsed compared with not relapsed HNSCC patients (P = 0.02 and P = 0.03). Anti-EGFR treatments inhibited the drainage-induced proliferation, with the highest inhibitory efficiency by cetuximab on A431 cells, while CAL27 cell growth was more efficiently inhibited by tyrosine kinase inhibitors.
  
  
  CONCLUSIONS
  Surgery could favor the proliferation of cells showing EGFR overexpression/activation/amplification such as residual tumor cells and/or precursor-field epithelial cells already present after surgery. Treatment with anti-EGFR reagents inhibits wound-induced stimulation, according to the EGFR family status.
authors.affiliation: Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Licitra
authors.forename: F
authors.initials: F
authors.lastname: Perrone
authors.forename: E
authors.initials: E
authors.lastname: Tamborini
authors.forename: L
authors.initials: L
authors.lastname: Bertola
authors.forename: C
authors.initials: C
authors.lastname: Ghirelli
authors.forename: T
authors.initials: T
authors.lastname: Negri
authors.forename: M
authors.initials: M
authors.lastname: Orsenigo
authors.forename: P
authors.initials: P
authors.lastname: Filipazzi
authors.forename: E
authors.initials: E
authors.lastname: Pastore
authors.forename: M
authors.initials: M
authors.lastname: Pompilio
authors.forename: P
authors.initials: P
authors.lastname: Bossi
authors.forename: L D
authors.initials: LD
authors.lastname: Locati
authors.forename: G
authors.initials: G
authors.lastname: Cantu'
authors.forename: G
authors.initials: G
authors.lastname: Scaramellini
authors.forename: S
authors.initials: S
authors.lastname: Pilotti
authors.forename: E
authors.initials: E
authors.lastname: Tagliabue
mesh_terms: D000328:Adult; D000368:Aged; D001826:Body Fluids / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000601:surgery; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000473:pathology* / Q000517:prevention & control; D009367:Neoplasm Staging; D018739:Oncogene Proteins v-erbB / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014945:Wound Healing
chemical_list: D066246:ErbB Receptors; D018739:Oncogene Proteins v-erbB; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human