title: Implantable tissue isolation chambers for analyzing tumor dynamics in vivo.
abstract: Recruitment of new blood vessels from the surrounding tissue is central to tumor progression and involves a fundamental transition of the normal, organized vasculature into a dense disarray of vessels that infiltrates the tumor. At present, studying the co-development of the tumor and recruited normal tissue is experimentally challenging because many of the important events occur rapidly and over short length scales in a dense three-dimensional space. To overcome these experimental limitations, we partially confined tumors within biocompatible and optically clear tissue isolation chambers (TICs) and implanted them in mice to create a system that is more amenable to microscopic analysis. Our goal was to integrate the tumor into a recruited host tissue - complete with vasculature - and demonstrate that the system recapitulates relevant features of the tumor microenvironment. We show that the TICs allow clear visualization of the cellular events associated with tumor growth and progression at the host-tumor interface including cell infiltration, matrix remodeling and angiogenesis. The tissue within the chamber is viable for more than a month, and the process is robust in both the skin and brain. Treatment with losartan, an angiotensin II receptor antagonist, decreased the collagen density and fiber length in the TIC, consistent with the known activity of this drug. We further show that collagen fibers display characteristic tumor signatures and play a central role in angiogenesis, guiding the migration of tethered endothelial sprouts. The methodology combines accessible methods of microfabrication with animal models and will enable more informative studies of the cellular mechanisms of tumor progression.
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. munn@steele.mgh.harvard.edu.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gruionu
authors.forename: Despina
authors.initials: D
authors.lastname: Bazou
authors.forename: Nir
authors.initials: N
authors.lastname: Maimon
authors.forename: Mara
authors.initials: M
authors.lastname: Onita-Lenco
authors.forename: Lucian G
authors.initials: LG
authors.lastname: Gruionu
authors.forename: Peigen
authors.initials: P
authors.lastname: Huang
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D001808:Blood Vessels / Q000473:pathology; D001921:Brain / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004129:Dimethylpolysiloxanes; D004867:Equipment Design; D005347:Fibroblasts / Q000473:pathology; D020007:Implants, Experimental; D019808:Losartan; D008264:Macrophages / Q000473:pathology; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D009924:Organ Culture Techniques / Q000295:instrumentation*; D017154:Stromal Cells / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D001672:Biocompatible Materials; D004129:Dimethylpolysiloxanes; D003094:Collagen; D019808:Losartan