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Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema

Affiliation
Laboratory of Tumor and Development Biology ,GIGA-Cancer ,University of Liège (ULiège) ,Sart-Tilman ,Liège ,Belgium
Buntinx, F.;
Affiliation
Laboratory of Tumor and Development Biology ,GIGA-Cancer ,University of Liège (ULiège) ,Sart-Tilman ,Liège ,Belgium
Lebeau, A.;
Affiliation
Laboratory of Tumor and Development Biology ,GIGA-Cancer ,University of Liège (ULiège) ,Sart-Tilman ,Liège ,Belgium
Gillot, L.;
Affiliation
Laboratory of Tumor and Development Biology ,GIGA-Cancer ,University of Liège (ULiège) ,Sart-Tilman ,Liège ,Belgium
Baudin, L.;
Affiliation
Laboratory of Tumor and Development Biology ,GIGA-Cancer ,University of Liège (ULiège) ,Sart-Tilman ,Liège ,Belgium
Ndong Penda, R.;
Affiliation
U1297-Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) ,Institut National de la Santé et de la Recherche Médicale (INSERM) ,University of Toulouse ,Toulouse ,France
Morfoisse, F.;
Affiliation
Laboratory of Tumor and Development Biology ,GIGA-Cancer ,University of Liège (ULiège) ,Sart-Tilman ,Liège ,Belgium
Lallemand, F.;
Affiliation
Department of Plastic and Reconstructive Surgery ,Centre Hospitalier Universitaire (CHU) de Liège ,University of Liège ,Liège ,Belgium
Vottero, G.;
Affiliation
Department of Plastic and Reconstructive Surgery ,Centre Hospitalier Universitaire (CHU) de Liège ,University of Liège ,Liège ,Belgium
Nizet, C.;
Affiliation
Department of Plastic and Reconstructive Surgery ,Centre Hospitalier Universitaire (CHU) de Liège ,University of Liège ,Liège ,Belgium
Nizet, J. L.;
Affiliation
Laboratory of Tumor and Development Biology ,GIGA-Cancer ,University of Liège (ULiège) ,Sart-Tilman ,Liège ,Belgium
Blacher, S.;
Affiliation
Laboratory of Tumor and Development Biology ,GIGA-Cancer ,University of Liège (ULiège) ,Sart-Tilman ,Liège ,Belgium
Noel, A.

Lymphedema (LD) refers to a condition of lymphatic dysfunction associated with excessive fluid accumulation, fibroadipose tissue deposition and swelling. In industrialized countries, LD development mainly results from a local disruption of the lymphatic network by an infection or cancer-related surgery (secondary LD). In the absence of efficient therapy, animal models are needed to decipher the cellular and molecular mechanisms underlying LD and test putative drugs. In this study, we optimized and characterized a murine model of LD that combines an irradiation of the mice hind limb and a radical surgery (lymph node resection associated to lymphatic vessel ligation). We investigated the respective roles of irradiation and surgery in LD formation by comparing their impacts, alone or in combination (with different intervention sequences), on eight different features of the pathology: swelling (paw thickness), indocyanine green (ICG) clearance, lymphatic vasculature remodeling, epidermal and dermal thickening, adipocyte accumulation, inflammatory cell infiltration and collagen deposition. This study supports the importance of radiation prior to surgery to experimentally induce a rapid, severe and sustained tissue remodeling harboring the different hallmarks of LD. We provide the first experimental evidence for an excessive deposition of periostin (POSTN) and tenascin-C (TNC) in LD. Through a computerized method of digital image quantification, we established the spatial map of lymphatic expansion, as well as collagen, POSTN and TNC deposition in papillary and reticular dermis of lymphedematous skins. This mouse model is available to study the patho-physiology of LD and test potential therapeutic targets.

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License Holder: Copyright © 2022 Buntinx, Lebeau, Gillot, Baudin, Ndong Penda, Morfoisse, Lallemand, Vottero, Nizet, Nizet, Blacher and Noel.

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