Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling

Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, M., Erler, J. T., Fong, S. F. T., Csiszar, K., Giaccia, A., Weninger, W., Yamauchi, M., Gasser, D. L., Weaver, V. M. (2009) Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling. Cell, 139 (5). pp. 891-906. ISSN 00928674 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/19931152
DOI: 10.1016/j.cell.2009.10.027

Abstract

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy. © 2009 Elsevier Inc. All rights reserved.

Item Type: Paper
Uncontrolled Keywords: CELLBIO HUMDISEASE collagen growth factor integrin phosphatidylinositol 3 kinase animal cell animal experiment animal model animal tissue article breast cancer breast carcinogenesis cancer incidence cancer invasion cross linking enzyme activity epithelium extracellular matrix female fibrosis focal adhesion mouse neoplasm nonhuman oncogene precancer priority journal protein cross linking signal transduction tumor growth Aging Animals Breast Neoplasms Epidermal Growth Factor Genes, ras Humans Integrins Mammary Glands, Human Mice Mice, Inbred BALB C Protein-Lysine 6-Oxidase Mouse mammary tumor virus
Subjects: diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > integrin
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > matrix protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Egeblad lab
Depositing User: Matt Covey
Date: 2009
Date Deposited: 14 Mar 2013 19:39
Last Modified: 14 Mar 2013 19:39
PMCID: PMC2788004
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27811

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