Radiation-induced fibrosis: mechanisms and implications for therapy

Abstract

Purpose: Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition.

Methods: A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms.

Results: RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways.

Conclusion: Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.

Keywords: Cancer; Fibroblast; Fibrosis; Inflammation; Radiation; TGF-β; Therapy.

Fig. 1

Schematic depicting four broad stages in the pathogenesis of RIF. 1 Ionizing radiation damages cells in the exposed field and leads to the production of proinflammatory cytokines. 2 Neutrophils, lymphocytes, and monocytes arrive at the site of injury while resultant M2 macrophages produce PDGF, leading to recruitment of stromal fibroblasts as well as differentiation of circulating mesenchymal stem cells. 3 Subsequent TGF-β production by M2 macrophages promotes the development of myofibroblasts from recruited stromal fibroblasts through a protomyofibroblast intermediate as well as through epithelial–mesenchymal transition and differentiation of circulating fibrocytes. 4 Over time, myofibroblast proliferation along with excess deposition and decreased degradation of extracellular matrix leads to fibrosis with reduced vascularity and a paucity of cells