Extracellular Matrix Remodeling and Stiffening Modulate Tumor Phenotype and Treatment Response Jennifer L. Leight, 1, ∗ Allison P. Drain, 2, ∗ and Valerie M. Weaver 3 1 Department of Biomedical Engineering and The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210; email: leight.1@osu.edu 2 University of California, Berkeley–University of California, San Francisco Graduate Program in Bioengineering, Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, California 94143; email: adrain@berkeley.edu 3 Center for Bioengineering and Tissue Regeneration, Department of Surgery, Department of Anatomy, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California 94143; email: valerie.weaver@ucsf.edu Annu. Rev. Cancer Biol. 2017. 1:313–34 First published online as a Review in Advance on November 9, 2016 The Annual Review of Cancer Biology is online at cancerbio.annualreviews.org This article’s doi: 10.1146/annurev-cancerbio-050216-034431 Copyright c  2017 by Annual Reviews. All rights reserved ∗ These authors contributed equally to this work. Keywords extracellular matrix, remodeling, tissue stiffness, tumor microenvironment, cancer Abstract Solid tumors are characterized by a remodeled and stiffened extracellular matrix. The extracellular matrix is not a passive by-product of the tumor, but actively compromises tissue-specific differentiation, enhances tumor cell proliferation and survival, and fosters tumor cell invasion and migration. The tumor extracellular matrix also influences the behavior of the stromal cells, which through vicious, feedforward-reinforcing pathways promote tumor progression and compromise treatment efficacy. To investigate how the tu- mor extracellular matrix alters cancer phenotype and treatment, a number of three-dimensional, organotypic culture models have been developed that employ a variety of materials, including natural matrices, collagen, fibrin, and reconstituted basement membrane gels, as well as synthetic hydrogel materi- als such as polyacrylamide and polyethylene glycol. These models have been used to interrogate how specific microenvironmental features modify tumor and stromal cell function and to identify the molecular mechanisms that reg- ulate tumorigenesis and therapeutic efficacy. To translate these findings into more effective treatment strategies for patients, clinically informed studies are needed that incorporate computational modeling and in vivo validation. 313 Click here to view this article's online features: • Download figures as PPT slides • Navigate linked references • Download citations • Explore related articles • Search keywords ANNUAL REVIEWS Further Annu. Rev. Cancer Biol. 2017.1:313-334. Downloaded from www.annualreviews.org Access provided by 18.234.69.63 on 02/20/22. For personal use only.