title: Recapitulating the human tumor microenvironment: Colon tumor-derived extracellular matrix promotes angiogenesis and tumor cell growth.
abstract: Extracellular matrix (ECM) is an essential and dynamic component of all tissues and directly affects cellular behavior by providing both mechanical and biochemical signaling cues. Changes in ECM can alter tissue homeostasis, potentially leading to promotion of cellular transformation and the generation of tumors. Therefore, understanding ECM compositional changes during cancer progression is vital to the development of targeted treatments. Previous efforts to reproduce the native 3D cellular microenvironment have utilized protein gels and scaffolds that incompletely recapitulate the complexity of native tissues. Here, we address this problem by extracting and comparing ECM from normal human colon and colon tumor that had metastasized to liver. We found differences in protein composition and stiffness, and observed significant differences in vascular network formation and tumor growth in each of the reconstituted matrices, both in vitro and in vivo. We studied free/bound ratios of NADH in the tumor and endothelial cells using Fluorescence Lifetime Imaging Microscopy as a surrogate for the metabolic state of the cells. We observed that cells seeded in tumor ECM had higher relative levels of free NADH, consistent with a higher glycolytic rate, than those seeded in normal ECM. These results demonstrate that the ECM plays an important role in the growth of cancer cells and their associated vasculature.
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA.
authors.forename: Mónica
authors.initials: M
authors.lastname: Romero-López
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Trinh
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA.
authors.forename: Agua
authors.initials: A
authors.lastname: Sobrino
authors.affiliation: Department of Molecular Biology and Biochemistry, School of Biological Sciences, UC Irvine, USA.
authors.forename: Michaela M S
authors.initials: MM
authors.lastname: Hatch
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Keating
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA.
authors.forename: Cristhian
authors.initials: C
authors.lastname: Fimbres
authors.affiliation: Department of Molecular Biology and Biochemistry, School of Biological Sciences, UC Irvine, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Lewis
authors.affiliation: Department of Molecular Biology and Biochemistry, School of Biological Sciences, UC Irvine, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gershon
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA; The Edwards Lifesciences Center for Advanced Cardiovascular Technology, UC Irvine, USA.
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Botvinick
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Digman
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA; Department of Mathematics, School of Physical Sciences, UC Irvine, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Lowengrub
authors.affiliation: Department of Biomedical Engineering, The Henry Samueli School of Engineering, UC Irvine, USA; Department of Molecular Biology and Biochemistry, School of Biological Sciences, UC Irvine, USA; The Edwards Lifesciences Center for Advanced Cardiovascular Technology, UC Irvine, USA. Electronic address: cchughes@uci.edu.
authors.forename: Christopher C W
authors.initials: CC
authors.lastname: Hughes
mesh_terms: D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000473:pathology* / Q000503:physiopathology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
keywords: 3D cell culture; Colon; Decellularization; ECM; Tumor metabolism; Tumor microenviroment