Three‐dimensional matrix stiffness and adhesive ligands affect cancer cell response to toxins. Issue 2 (3rd September 2015)

• Record Type: Journal Article
• Authors: Zustiak, Silviya Petrova; Dadhwal, Smritee; Medina, Carlos; Steczina, Sonette; Chehreghanianzabi, Yasaman; Ashraf, Anisa; Asuri, Prashanth
• Is Part Of: Biotechnology and bioengineering. Volume 113:Issue 2(2016)
• Page Start: 443
• Page End: 452
• Publication Date: 2015-09-03
• Subjects: 3D cell culture -- matrix stiffness -- cell‐matrix adhesions -- drug toxicity -- cancer drug screening; Biotechnology -- Periodicals; Bioengineering -- Periodicals; 660.6
• DOI: 10.1002/bit.25709
• Languages: English
• ISSNs: 0006-3592

Abstract

ABSTRACT: There is an immediate need to develop highly predictive in vitro cell‐based assays that provide reliable information on cancer drug efficacy and toxicity. Development of biomaterial‐based three‐dimensional (3D) cell culture models as drug screening platforms has recently gained much scientific interest as 3D cultures of cancer cells have been shown to more adequately mimic the in vivo tumor conditions. Moreover, it has been recognized that the biophysical and biochemical properties of the 3D microenvironment can play key roles in regulating various cancer cell fates, including their response to chemicals. In this study, we employed alginate‐based scaffolds of varying mechanical stiffness and adhesive ligand presentation to further explore the role of 3D microenvironmental cues on glioblastoma cell response to cytotoxic compounds. Our experiments suggested the ability of both matrix stiffness and cell‐matrix adhesions to strongly influence cell responses to toxins. Cells were found to be more susceptible to the toxins when cultured in softer matrices that emulated the stiffness of brain tissue. Furthermore, the effect of matrix stiffness on differential cell responses to toxins was negated by the presence of the adhesive ligand RGD, but regained when integrin‐based cell‐matrix interactions were inhibited. This study therefore indicates that both 3D matrix stiffness and cell‐matrix adhesions are important parameters in the design of more predictive in vitro platforms for drug development and toxicity screening. Biotechnol. Bioeng. 2016;113: 443–452. © 2015 Wiley Periodicals, Inc. Abstract : Using human glioblastoma cells encapsulated in alginate hydrogels of varying stiffness and adhesive ligand presentation, the authors demonstrate that both matrix stiffness and cell‐matrix adhesions influence cell response to toxic chemicals. This study addresses the need to develop combinatorial assays that study the influence of in vivo‐like cues on cancer cell responses to drugs for the design of predictive in vitro platforms for drug screening.