title: The timing of surgery after neoadjuvant radiotherapy influences tumor dissemination in a preclinical model.
abstract: Neoadjuvant radiotherapy (neoRT) used in cancer treatments aims at improving local tumor control and patient overall survival. The neoRT schedule and the timing of the surgical treatment (ST) are empirically based and influenced by the clinician's experience. The current study examines how the sequencing of neoRT and ST affects metastatic dissemination. In a breast carcinoma model, tumors were exposed to different neoRT schedules (2x5Gy or 5x2Gy) followed by surgery at day 4 or 11 post-RT. The impact on the tumor microenvironment and lung metastases was evaluated through immunohistochemical and flow cytometry analyses. After 2x5Gy, early ST (at day 4 post-RT) led to increased size and number of lung metastases as compared to ST performed at day 11. Inversely, after 5x2Gy neoRT, early ST protected the mice against lung metastases. This intriguing relationship between tumor aggressiveness and ST timing could not be explained by differences in classical parameters studied such as hypoxia, vessel density and matrix remodeling. The study of tumor-related inflammation and immunity reveals an increased circulating NK cell percentage following neoRT as compared to non irradiated mice. Then, radiation treatment and surgery were applied to tumor-bearing NOD/SCID mice. In the absence of NK cells, neoRT appears to increase lung metastatic dissemination as compared to non irradiated tumor-bearing mice. Altogether our data demonstrate that the neoRT schedule and the ST timing affect metastasis formation in a pre-clinical model and points out the potential role of NK cells. These findings highlight the importance to cautiously tailor the optimal window for ST following RT.
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Belgium.|Department of Radiotherapy-Oncology, Centre Hospitalier Universitaire (CHU) de Liège, Belgium.
authors.forename: Natacha
authors.initials: N
authors.lastname: Leroi
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Belgium.
authors.forename: Nor Eddine
authors.initials: NE
authors.lastname: Sounni
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium.|Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Van Overmeire
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.affiliation: Systems and Modeling (GIGA-Systems Biology and Chemical Biology), University of Liège, Belgium.|GIGA Bioinformatics Platform, University of Liège, Belgium.
authors.forename: Raphael
authors.initials: R
authors.lastname: Marée
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium.|Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Van Ginderachter
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Lallemand
authors.affiliation: Department of Radiotherapy-Oncology, Centre Hospitalier Universitaire (CHU) de Liège, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Lenaerts
authors.affiliation: Department of Radiotherapy-Oncology, Centre Hospitalier Universitaire (CHU) de Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Coucke
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Belgium.|Department of Radiotherapy-Oncology, Centre Hospitalier Universitaire (CHU) de Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Martinive
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000532:radiotherapy / Q000556:secondary* / Q000601:surgery / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D018714:Radiotherapy, Adjuvant; D013997:Time Factors; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
keywords: NK cells; lung metastases; neoadjuvant radiotherapy; tumor microenvironment; tumor surgery