Preventing Radiation-Induced Capsular Contracture with a Class of Novel Antifibrotics
Trevor Hansen, MD, Katie Lannan, PhD, Collynn Woeller, PhD, Rachel Park, BS, Richard Phipps, PhD, Howard Langstein, MD.
University of Rochester, Rochester, NY, USA.
Background: Capsular contracture is a serious and painful complication that affects breast cancer patients following implant-based reconstruction. Adjuvant radiotherapy, while important in destroying residual cancer cells, exacerbates capsular contracture and scar formation. Capsular contracture is driven by aberrant myofibroblast accumulation and differentiation, marked by increased production of alpha-smooth muscle actin (αSMA), and deposition of extracellular matrix proteins, such as collagen. Here, we tested a class of polyether ionophores with novel antifibrotic properties, including salinomycin (SNC), narasin (NAR), and monensin (MNS), for their ability to prevent myofibroblast differentiation in vitro and subsequent scar formation in two in vivo models of capsular contracture.
Methods: We cultured fibroblasts isolated from primary human breast capsule tissue and induced myofibroblast differentiation and activation with transforming growth factor beta (TGFβ) with or without radiation. Samples were then treated with polyether ionophores or not and analyzed for expression of myofibroblast markers. To test if polyether ionophores can block myofibroblast mediated scarring in vivo, a novel animal model of radiation-induced capsular fibrosis was utilized, wherein silicone implants were surgically placed in a submuscular pocket on the backs of mice followed by radiation or not to instigate a fibrotic reaction. Polyether ionophores were delivered either orally or locally to test their in vivo efficacy. The resulting peri-implant capsules were then harvested for histologic and protein analysis.
Results: All polyether ionophores reduced αSMA expression in response to TGF beta with or without radiation. Additionally, immunofluorescent imaging demonstrated reduced myofibroblast phenotype. In the in vivo model of radiation-induced capsular fibrosis, all three compounds significantly reduced peri-implant thickness when delivered orally. This was associated with reduced collagen mRNA levels as compared to untreated controls. Localized administration of SNC directly to the silicone implant site at time of surgery was also effective in reducing scar formation.
Conclusions: These exciting new data suggest that select polyether ionophores are potential new therapeutics to combat debilitating capsular contracture associated with radiation and/or silicone implants. Additionally, they can affect scar deposition when delivered systemically or locally. While additional studies are required to determine the efficacy and feasibility of such treatments in humans, these data demonstrate a promising novel treatment for capsular contracture.
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