title: Three-dimensional matrix stiffness and adhesive ligands affect cancer cell response to toxins.
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.
authors.affiliation: Department of Biomedical Engineering, Saint Louis University, St. Louis, Missouri.
authors.forename: Silviya Petrova
authors.initials: SP
authors.lastname: Zustiak
authors.affiliation: Department of Bioengineering, Santa Clara University, Santa Clara, California.
authors.forename: Smritee
authors.initials: S
authors.lastname: Dadhwal
authors.affiliation: Department of Bioengineering, Santa Clara University, Santa Clara, California.
authors.forename: Carlos
authors.initials: C
authors.lastname: Medina
authors.affiliation: Department of Bioengineering, Santa Clara University, Santa Clara, California.
authors.forename: Sonette
authors.initials: S
authors.lastname: Steczina
authors.affiliation: Department of Biomedical Engineering, Saint Louis University, St. Louis, Missouri.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Chehreghanianzabi
authors.affiliation: Department of Biomedical Engineering, Saint Louis University, St. Louis, Missouri.
authors.forename: Anisa
authors.initials: A
authors.lastname: Ashraf
authors.affiliation: Department of Bioengineering, Santa Clara University, Santa Clara, California. asurip@scu.edu.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Asuri
mesh_terms: D000464:Alginates; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy*; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D006801:Humans; D008954:Models, Biological; D054457:Tissue Scaffolds
chemical_list: D000464:Alginates; D000970:Antineoplastic Agents; D006603:Hexuronic Acids; D020723:Glucuronic Acid
keywords: 3D cell culture; cancer drug screening; cell-matrix adhesions; drug toxicity; matrix stiffness