Clinical Research Papers:
The timing of surgery after neoadjuvant radiotherapy influences tumor dissemination in a preclinical model
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Natacha Leroi1,2, Nor Eddine Sounni1, Eva Van Overmeire3,4, Silvia Blacher1, Raphael Marée5,6, Jo Van Ginderachter3,4, François Lallemand1, Eric Lenaerts2, Philippe Coucke2, Agnès Noel1,* and Philippe Martinive1,2,*
1 Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liege, Belgium
2 Department of Radiotherapy-Oncology, Centre Hospitalier Universitaire (CHU) de Liège, Belgium
3 Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium
4 Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
5 Systems and Modeling (GIGA-Systems Biology and Chemical Biology), University of Liège, Belgium
6 GIGA Bioinformatics Platform, University of Liège, Belgium
* co-senior authors
Philippe Martinive, email:
Keywords: neoadjuvant radiotherapy, tumor microenvironment, tumor surgery, lung metastases, NK cells
Received: June 28, 2015 Accepted: September 15, 2015 Published: September 30, 2015
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.
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