10.3 Radiation-induced fibrosis and tissue remodeling
4 min read•july 31, 2024
is a long-term side effect of cancer treatment that can seriously impact patients' lives. It happens when too much collagen builds up in tissues after radiation, making them stiff and less functional. This process can affect various organs, from skin to lungs to heart.
Understanding how fibrosis develops is crucial for improving cancer care. Scientists are studying the molecular pathways involved and working on ways to detect and treat it early. Managing fibrosis often requires a team approach, combining different therapies to help patients maintain quality of life after radiation.
Radiation-induced fibrosis
Definition and characteristics
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Radiation-induced fibrosis manifests as a chronic, progressive condition characterized by excessive deposition of extracellular matrix components (collagen) in irradiated tissues
Fibrosis emerges as a major component of late radiation effects, typically appearing months to years after radiation exposure
Development of fibrosis results in tissue stiffness, reduced elasticity, and impaired organ function in affected areas
Fibrosis can occur in various organs and tissues (skin, lungs, heart, gastrointestinal tract)
Severity and extent of fibrosis depend on factors such as total radiation dose, fractionation schedule, and individual patient susceptibility
Fibrosis contributes significantly to long-term morbidity in cancer survivors who have undergone radiotherapy treatments
Impact on tissue function
Excessive leads to altered tissue architecture and compromised organ functionality
Reduced tissue elasticity impairs normal physiological processes (breathing in lung fibrosis, cardiac contractility in heart fibrosis)
Fibrotic changes can cause tissue contraction and deformity (skin contractures, bowel strictures)
Vascular changes associated with fibrosis may lead to reduced blood supply and tissue hypoxia
Fibrosis can interfere with normal cellular functions and tissue homeostasis
Progressive nature of fibrosis can result in gradual deterioration of organ function over time
Molecular mechanisms of fibrosis
Cellular response to radiation damage
Radiation-induced DNA damage triggers a complex cascade of cellular and molecular events leading to fibrosis
Activation of pro-fibrotic cytokines, particularly transforming growth factor-beta (TGF-β), plays a central role in initiating and sustaining the fibrotic process
Chronic inflammation and oxidative stress contribute to the perpetuation of the fibrotic response
Radiation exposure leads to phenotypic changes in fibroblasts, transforming them into , which are key effector cells in fibrosis
Myofibroblasts produce excessive amounts of extracellular matrix proteins (collagens, fibronectin, proteoglycans)
Endothelial cell damage and vascular changes play a role in tissue hypoxia and perpetuation of the fibrotic process
Molecular pathways and mediators
TGF-β signaling pathway activation leads to increased production of extracellular matrix proteins
Upregulation of pro-fibrotic genes (COL1A1, COL3A1, CTGF) through SMAD-dependent and SMAD-independent pathways
Activation of other pro-fibrotic mediators (PDGF, CTGF, IL-13) contributes to the fibrotic process
Dysregulation of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to aberrant
Increased expression of adhesion molecules (integrins) promotes and matrix deposition
Epigenetic changes, including DNA methylation and histone modifications, influence gene expression patterns in fibrosis
Tissue remodeling after radiation
Phases of tissue remodeling
Tissue remodeling involves a dynamic process of breakdown and reorganization of existing tissue structures in response to radiation-induced damage
Initial acute inflammation characterized by rapid influx of inflammatory cells and release of pro-inflammatory mediators (TNF-α, IL-1β)
Chronic inflammatory phase follows, with sustained infiltration of immune cells and ongoing release of inflammatory mediators
Radiation-induced cell death triggers compensatory proliferation and differentiation of surviving cells
Balance between extracellular matrix production and degradation becomes disrupted, leading to excessive matrix deposition
Vascular remodeling occurs, including changes in vessel density, permeability, and functionality (angiogenesis, vessel regression)
Consequences of tissue remodeling
Altered tissue architecture results in loss of organ-specific functions (reduced alveolar gas exchange in lung fibrosis)
Progressive nature of fibrosis results in delayed onset of symptoms, presenting challenges for long-term patient management
Fibrosis and tissue remodeling can limit options for future treatments (surgery, re-irradiation) in cases of cancer recurrence
Increased risk of treatment-related morbidity in subsequent cancer therapies
Potential impact on overall survival and disease-free survival in cancer patients
Management and future directions
Understanding mechanisms of radiation-induced fibrosis crucial for developing strategies to prevent or mitigate its effects
Current research focuses on identifying biomarkers for early detection of fibrosis (circulating microRNAs, specific cytokine profiles)
Development of targeted therapies to modulate the fibrotic process (TGF-β inhibitors, antioxidants)
Management of radiation-induced fibrosis often requires a multidisciplinary approach (supportive care, physical therapy, pharmacological interventions)
Emerging treatments include stem cell therapies and tissue engineering approaches to promote regeneration
Importance of long-term follow-up and monitoring of cancer survivors for late effects of radiotherapy
Ongoing efforts to optimize radiation treatment planning to minimize risk of fibrosis while maintaining therapeutic efficacy