Article

The impact of Smad3 loss of function on TGF-β signaling and radiation-induced capsular contracture.

Division of Plastic and Reconstructive Surgery, Department of General Surgery, the Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
Plastic and Reconstructive Surgery (Impact Factor: 3.33). 06/2011; 127(6):2263-9. DOI: 10.1097/PRS.0b013e3182131bea
Source: PubMed

ABSTRACT Capsular contracture remains a major problem following prosthetic breast implantation, especially in patients undergoing irradiation. Recent studies suggest that such radiation injuries are a cascading process of cytokine activation, with transforming growth factor (TGF)-β acting as the "master switch." Because TGF-β signals through phosphorylation of Smad3, a plausible approach to abate TGF-β-induced capsular contracture would be to interrupt Smad3 signaling. To test this hypothesis, capsular contracture formation in wild-type and Smad3 knockout mice was compared using micro-computed tomographic and histologic examination.
On day 0, 48 mice were implanted with bilateral silicone gel implants. Postoperatively, animals were imaged using live-scan micro-computed tomographic scanning. Animals in the radiation arm then received a 10-Gy directed radiation dose. On postoperative days 21, 28, 35, and 42, animals were imaged again. Histologic evaluation was performed at necropsy.
Irradiated implants in the wild-type mice demonstrated shape and contour deformation on micro-computed tomographic scanning beginning on postoperative day 21 and progressing through day 42. Conversely, micro-computed tomographic scanning of irradiated implants in knockout mice demonstrated few changes from day 0 through day 42. Corresponding histologic specimens from wild-type mice demonstrated irregular capsules composed of disorganized collagen that became thicker from day 21 to day 42. Irradiated knockout specimen maintained thin capsules from day 21 through day 42.
In this work, inhibiting TGF-β signaling led to a reduction in radiation-induced capsular contracture as measured by micro-computed tomographic and histologic evaluation. The results of this study suggest a promising target for the prevention of capsular contracture through the development of anti-Smad3/TGF-β-based therapies.

0 Bookmarks
 · 
120 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Radiotherapy side-effects diminish patients? quality of life, yet effective biological interventions for normal tissue damage are lacking. Protecting microvascular endothelial cells from the effects of irradiation is emerging as a targeted damage-reduction strategy. We illustrate the concept of the microvasculature as a mediator of overall normal tissue radiation toxicity through cell death, vascular inflammation (hemodynamic and molecular changes) and functional capacity. Endothelial cell targeted therapies that protect against such endothelial cell perturbations and the development of acute normal tissue damage are mostly under preclinical development. Since acute radiation toxicity is a common clinical problem in cutaneous, gastrointestinal and mucosal tissues, we also focus on damage in these tissues.
    Radiation Oncology 12/2014; 9:266. · 2.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Acute skin damage from cancer radiotherapy diminishes patients' quality of life, yet effective biological interventions for this damage are lacking. Protecting microvascular endothelial cells from irradiation-induced perturbations is emerging as a targeted damage-reduction strategy. Since Angiopoetin-1 signaling through the Tie2 receptor on endothelial cells opposes microvascular perturbations in other disease contexts, we used a preclinical Angiopoietin-1 mimic called Vasculotide to investigate its effect on skin radiation toxicity using a preclinical model.
    BMC Cancer 08/2014; 14(1):614. · 3.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinicians and investigators have been implanting biomedical devices into patients and experimental animals for centuries. There is a characteristic complex inflammatory response to the presence of the biomedical device with diverse cell signaling, followed by migration of fibroblasts to the implant surface and the eventual walling off of the implant in a collagen capsule. If the device is to interact with the surrounding tissues, the collagen envelope will eventually incapacitate the device or myofibroblasts can cause capsular contracture with resulting distortion, migration, or firmness. This review analyzes the various tactics used in the past to modify or control capsule formation with suggestions for future investigative approaches.
    Annals of plastic surgery. 07/2014;