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19 January 2018 Development and Characterization of an In Vitro Model for Radiation-Induced Fibrosis
Dhruv Kumar, Sreeya Yalamanchali, Jacob New, Sean Parsel, Natalie New, Andrew Holcomb, Sumedha Gunewardena, Ossama Tawfik, Chris Lominska, Bruce F. Kimler, Shrikant Anant, Kiran Kakarala, Terance Tsue, Yelizaveta Shnayder, Kevin Sykes, Subhash Padhye, Sufi Mary Thomas
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Abstract

Radiation-induced fibrosis (RIF) is a major side effect of radiotherapy in cancer patients with no effective therapeutic options. RIF involves excess deposition and aberrant remodeling of the extracellular matrix (ECM) leading to stiffness in tissues and organ failure. Development of preclinical models of RIF is crucial to elucidate the molecular mechanisms regulating fibrosis and to develop therapeutic approaches. In addition to radiation, the main molecular perpetrators of fibrotic reactions are cytokines, including transforming growth factor-β (TGF-β). We hypothesized that human oral fibroblasts would develop an in vitro fibrotic reaction in response to radiation and TGF-β. We demonstrate here that fibroblasts exposed to radiation followed by TGF-β exhibit a fibrotic phenotype with increased collagen deposition, cell proliferation, migration and invasion. In this in vitro model of RIF (RIFiv), the early biological processes involved in fibrosis are demonstrated, along with increased levels of several molecules including collagen 1α1, collagen XIα1, integrin-α2 and cyclin D1 mRNA in irradiated cells. A clinically relevant antifibrotic agent, pentoxifylline, and a curcumin analogue both mitigated collagen deposition in irradiated fibroblast cultures. In summary, we have established an in vitro model for RIF that facilitates the elucidation of molecular mechanisms in radiation-induced fibrosis and the development of effective therapeutic approaches.

©2018 by Radiation Research Society.
Dhruv Kumar, Sreeya Yalamanchali, Jacob New, Sean Parsel, Natalie New, Andrew Holcomb, Sumedha Gunewardena, Ossama Tawfik, Chris Lominska, Bruce F. Kimler, Shrikant Anant, Kiran Kakarala, Terance Tsue, Yelizaveta Shnayder, Kevin Sykes, Subhash Padhye, and Sufi Mary Thomas "Development and Characterization of an In Vitro Model for Radiation-Induced Fibrosis," Radiation Research 189(3), 326-336, (19 January 2018). https://doi.org/10.1667/RR14926.1
Received: 30 August 2017; Accepted: 1 November 2017; Published: 19 January 2018
JOURNAL ARTICLE
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