title: Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding.
abstract: OBJECTIVE
  After apparently successful excision of breast cancer, risk of local recurrence remains high mainly in the area surrounding the original tumor, indicating that wound healing processes may be implicated. The proportional reduction of this risk by radiotherapy does not depend on the extent of surgery, suggesting that radiotherapy, in addition to killing tumor cells, may influence the tumor microenvironment.
  
  
  METHODS
  We studied how normal and mammary carcinoma cell growth and motility are affected by surgical wound fluids (WF), collected over 24 h following breast-conserving surgery in 45 patients, 20 of whom had received additional TARGeted Intraoperative radioTherapy (TARGIT), immediately after the surgical excision. The proteomic profile of the WF and their effects on the activation of intracellular signal transduction pathways of breast cancer cells were also analyzed.
  
  
  RESULTS
  WF stimulated proliferation, migration, and invasion of breast cancer cell lines. The stimulatory effect was almost completely abrogated when fluids from TARGIT-treated patients were used. These fluids displayed altered expression of several cytokines and failed to properly stimulate the activation of some intracellular signal transduction pathways, when compared with fluids harvested from untreated patients.
  
  
  CONCLUSIONS
  Delivery of TARGIT to the tumor bed alters the molecular composition and biological activity of surgical WF. This novel antitumoral effect could, at least partially, explain the very low recurrence rates found in a large pilot study using TARGIT. It also opens a novel avenue for identifying new molecular targets and testing novel therapeutic agents.
authors.affiliation: Experimental Oncology, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.forename: Jayant S
authors.initials: JS
authors.lastname: Vaidya
authors.forename: Sara
authors.initials: S
authors.lastname: D'Andrea
authors.forename: Frank
authors.initials: F
authors.lastname: Entschladen
authors.forename: Mario
authors.initials: M
authors.lastname: Roncadin
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Stefania
authors.initials: S
authors.lastname: Berton
authors.forename: Tiziana
authors.initials: T
authors.lastname: Perin
authors.forename: Ezio
authors.initials: E
authors.lastname: Candiani
authors.forename: Sonia
authors.initials: S
authors.lastname: Reccanello
authors.forename: Andrea
authors.initials: A
authors.lastname: Veronesi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Canzonieri
authors.forename: Mauro G
authors.initials: MG
authors.lastname: Trovò
authors.forename: Kurt S
authors.initials: KS
authors.lastname: Zaenker
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.forename: Samuele
authors.initials: S
authors.lastname: Massarut
mesh_terms: D000818:Animals; D001940:Breast / Q000166:cytology / Q000528:radiation effects; D001943:Breast Neoplasms / Q000473:pathology* / Q000532:radiotherapy* / Q000601:surgery; D002465:Cell Movement; D049109:Cell Proliferation / Q000528:radiation effects*; D002478:Cells, Cultured; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000166:cytology / Q000528:radiation effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007430:Intraoperative Care; D008321:Mammary Glands, Animal / Q000166:cytology / Q000528:radiation effects; D015412:Mastectomy, Segmental; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D010865:Pilot Projects; D040901:Proteomics; D011879:Radiotherapy Dosage; D014471:Umbilical Veins / Q000166:cytology / Q000528:radiation effects