CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages

Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM–cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets

An essential role for decorin in bladder cancer invasiveness

Muscle-invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murine bladder tumour cell line MB49 and its more aggressive variant MB49-I, we demonstrate that the adaptive immune system efficiently limits progression of MB49, whereas MB49-I has lost tumour antigens and is insensitive to adaptive immune responses. Furthermore, we unravel a parallel mechanism developed by MB49-I to subvert its environment: de novo secretion of the proteoglycan decorin. We show that decorin overexpression in the MB49/MB49-I model is required for efficient progression, by promoting angiogenesis and tumour cell invasiveness. Finally, we show that these results are relevant to muscle-invasive human bladder carcinomas, which overexpress decorin together with angiogenesis- and adhesion/migration-related genes, and that decorin overexpression in the human bladder carcinoma cell line TCCSUP is required for efficient invasiveness in vitro. We thus propose decorin as a new therapeutic target for these aggressive tumours.Fil: El Behi, Mohamed. Institute Curie; Francia. Centre de Recherche de I; Francia. Inserm; FranciaFil: Krumeich, Sophie. Institute Curie; Francia. Inserm; FranciaFil: Lodillinsky, Catalina. Institute Curie; Francia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kamoun, Aurélie. Institute Curie; FranciaFil: Tibaldi, Lorenzo. Institute Curie; Francia. Inserm; FranciaFil: Sugano, Gaël. Institute Curie; Francia. Inserm; FranciaFil: de Reynies, Aurélien. Ligue Nationale Contre le Cancer; FranciaFil: Chapeaublanc, Elodie. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Laplanche, Agnès. Centre National de la Recherche Scientifique; Francia. Institut de Cancérologie Gustave Roussy; FranciaFil: Lebret, Thierry. Hôpital Foch. Service d; Francia. Université de Versailles; FranciaFil: Allory, Yves. Inserm; FranciaFil: Radvanyi, François. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Lantz, Olivier. Institute Curie; Francia. Inserm; FranciaFil: Eijan, Ana Maria. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bernard Pierrot, Isabelle. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Théery, Clotilde. Institute Curie; Francia. Inserm; Franci

Rôle de MFG-E8/lactadhérine dans la croissance tumorale

La lactadhérine/MfgeS est une protéine sécrétée favorisant l'angiogénèse médiée par le VEGF et l'élimination des corps apoptotiques par les phagocytes, qui induit des réponses immunitaires tolérogéniques. Ces deux processus étant importants dans le développement du cancer, cette thèse a donc pour but d'étudier l'importance de la lactadhérine dans la croissance tumorale. Dans un modèle de carcinogénèse chimioinduite de tumeurs de la vessie, nous avons décrit un rôle pro-tumoral de la lactadhérine, principalement via l'induction d'une réponse immunitaire tolérogénique. Ces données corrèlent avec les données de deux banques de tumeurs de vessie humaines. Dans un second modèle de carcinogénèse génétique, nous n'avons pas observé de rôle majeur de la lactadhérine dans la croissance de tumeurs de l'intestin, bien que la lactadhérine soit fortement exprimée dans ces tumeurs. Ces travaux fournissent donc une base intéressante pour des thérapies anti-tumorales dans les cancers de vessie.MfgeS/lactadherin is a secreted protein promoting VEGF-mediated angiogenesis and removal of apoptotic bodies by phagocytes, which induce tolerogenic immune responses. These two processes being important in cancer development, this thesis therefore aims to study lactadherin importance in tumor growth. In a chemoinduced carcinogenic model of bladder tumors, we have described a pro-tumoral role for lactadherin, mainly through induction of a tolerogenic immune response. These data correlate with two human bladder tumor banks. In a second model of genetic carcinogenesis, we did not observe a major role for lactadherin in intestine tumors growth, even if lactadherin is strongly expressed in these tumors. Thus, these works provide an interesting basis for anti-tumoral therapies in bladder cancers.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF