title: Surgery-induced wound response promotes stem-like and tumor-initiating features of breast cancer cells, via STAT3 signaling.
abstract: Inflammation is clinically linked to cancer but the mechanisms are not fully understood. Surgery itself elicits a range of inflammatory responses, suggesting that it could represent a perturbing factor in the process of local recurrence and/or metastasis. Post-surgery wound fluids (WF), drained from breast cancer patients, are rich in cytokines and growth factors, stimulate the in vitro growth of breast cancer cells and are potent activators of the STAT transcription factors. We wondered whether STAT signaling was functionally involved in the response of breast cancer cells to post-surgical inflammation. We discovered that WF induced the enrichment of breast cancer cells with stem-like phenotypes, via activation of STAT3. In vitro, WF highly stimulated mammosphere formation and self-renewal of breast cancer cells. In vivo, STAT3 signaling was critical for breast cancer cell tumorigenicity and for the formation of local relapse after surgery. Overall, we demonstrate here that surgery-induced inflammation promotes stem-like phenotypes and tumor-initiating abilities of breast cancer cells. Interfering with STAT3 signaling with a peri-surgical treatment was sufficient to strongly suppress this process. The understanding of the crosstalk between breast tumor-initiating cells and their microenvironment may open the way to successful targeting of these cells in their initial stages of growth and be eventually curative.
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Segatto
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Berton
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Sonego
authors.affiliation: Breast Surgery Unit, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Massarut
authors.affiliation: Pathology Unit, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Perin
authors.affiliation: Breast Surgery Unit, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Piccoli
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy; Department of Scienze Biologiche e Mediche, MATI Center of Excellence, University of Udine, 33100 Udine, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.affiliation: Division of Pathology, II University of Rome "La Sapienza", Santo Andrea Hospital, Rome 00189, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology / Q000528:radiation effects; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D014945:Wound Healing / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human