Physical forces from the extracellular matrix influence breast cancer cell response to doxorubicin

Date

2018-12-07

Authors

Joyce, Marshall Hunter

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Abstract

Cancer is a complex disease capable of affecting multiple organs and is driven by numerous factors. Certain ‘hallmarks of cancer’ have been identified which describe biological conditions that lead to tumor development and characteristics that often follow tumorigenesis. These hallmarks have been revisited to describe the role that the extracellular matrix (ECM) plays in each. Such observations make it evident that the ECM is an important factor in tumor initiation, progression, and metastasis and can no longer be ignored in the search for a cure. Studies aimed at characterizing the role physical cues play in tumor development have considered ligand variety, ligand density, substrate composition, and substrate stiffness. These studies frequently utilize hydrogels as a culture platform given the biological relevance and diversity achievable through such a platform. Though the stiffness of hydrogels can be attenuated at the onset of an experiment, few systems are able to alter stiffness once gelation is complete. This makes any study of progressive changes in ECM stiffness difficult and largely restricts the study of certain temporal aspects of tumor progression in vitro. Recently, a Matrigel-alginate hydrogel system has been described whereby progressive modulation of hydrogel stiffness can be achieved using liposomes loaded with gold nanorods and near infrared light. In this study we utilize this hydrogel system to thoroughly investigate the role that ECM stiffness has on breast cancer response to doxorubicin. We sought to observe how progressive stiffening of the ECM affected breast cancer cell response to clinically relevant chemotherapeutics in a system that allows for minimal perturbation of cells during the stiffening process. Our results showed that breast cancer cells exhibiting a mesenchymal phenotype had a stiffness-dependent resistance to the chemotherapeutic doxorubicin. Mathematical modeling was used to determine reduced growth rate alone was not sufficient to explain this stiffness-dependent resistance, suggesting an additional mechanism associated with the mesenchymal phenotype is responsible

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