Publication Date:
2015-05-15
Description:
The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch(+)Apc(+/1638N) mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and beta-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of beta-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by beta-catenin nuclear translocation after 15 days. As a consequence, increased expression of beta-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic beta-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandez-Sanchez, Maria Elena -- Barbier, Sandrine -- Whitehead, Joanne -- Bealle, Gaelle -- Michel, Aude -- Latorre-Ossa, Heldmuth -- Rey, Colette -- Fouassier, Laura -- Claperon, Audrey -- Brulle, Laura -- Girard, Elodie -- Servant, Nicolas -- Rio-Frio, Thomas -- Marie, Helene -- Lesieur, Sylviane -- Housset, Chantal -- Gennisson, Jean-Luc -- Tanter, Mickael -- Menager, Christine -- Fre, Silvia -- Robine, Sylvie -- Farge, Emmanuel -- England -- Nature. 2015 Jul 2;523(7558):92-5. doi: 10.1038/nature14329. Epub 2015 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie, Centre de Recherche, PSL Research University, CNRS UMR 168, Physicochimie Curie Mechanics and Genetics of Embryonic and Tumour Development, INSERM, Fondation Pierre-Gilles de Gennes, F-75005 Paris, France. ; UPMC, Sorbonne Universites, Laboratoire PHENIX Physico-chimie des Electrolytes et Nanosystemes Interfaciaux, CNRS UMR 8234, F-75005 Paris, France. ; Langevin Institut, Waves and Images ESPCI ParisTech, PSL Research University, CNRS UMR7587, Inserm U979. F-75005 Paris, France. ; Sorbonne Universites, UPMC and INSERM, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France. ; CNRS UMR3666/INSERM U1143, Endocytic Trafficking and Therapeutic Delivery, Institut Curie, Centre de Recherche, F-75005 Paris, France. ; Bioinformatic platform, U900, Institut Curie, MINES ParisTech, F-75005 Paris, France. ; Next-generation sequencing platform, Institut Curie, F-75005 Paris, France. ; CNRS UMR 8612, Laboratoire Physico-Chimie des Systemes Polyphases, Institut Galien Paris-Sud, LabEx LERMIT, Faculte de Pharmacie, Universite Paris-Sud, 92 296 Chatenay-Malabry, France. ; CNRS UMR 3215/INSERM U934, Unite de Genetique et Biologie du Developpement, Notch Signaling in Stem Cells and Tumors, Institut Curie, Centre de Recherche, F-75005 Paris, France. ; CNRS UMR144, Compartimentation et dynamique cellulaires, Morphogenesis and Cell Signalling Institut Curie, Centre de Recherche, F-75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970250" target="_blank"〉PubMed〈/a〉
Keywords:
Active Transport, Cell Nucleus
;
Animals
;
Carcinogenesis/*pathology
;
Colonic Neoplasms/*physiopathology
;
Epithelial Cells/cytology/pathology
;
Female
;
Gene Expression Regulation, Neoplastic
;
Magnets
;
Male
;
Metal Nanoparticles
;
Mice
;
Mice, Inbred C57BL
;
Phosphorylation
;
*Pressure
;
Proto-Oncogene Proteins c-ret/metabolism
;
Receptors, Notch/genetics/metabolism
;
Signal Transduction
;
*Tumor Microenvironment
;
beta Catenin/*genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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