Brown University researchers have published a new study in the journal Aging, which highlights the potential role of senescence-associated exosomes (SA-EXOs) in cancer-related fibrosis. The researchers examined how radiation-induced senescence alters the miRNA profiles of bone marrow-derived mesenchymal stem cells (MSCs), which accumulate in tumour sites due to their natural affinity for inflammatory and fibrotic tissues.
The study found that radiation-induced senescence led to the secretion of SA-EXOs, which contain unique miRNA content that modulates the TGF-β pathway and activates myofibroblast phenotypes. The researchers treated normal MSCs with SA-EXOs to examine the bystander effects of radiation-induced senescence and found that the modulated genes were related to the TGF-β pathway, with increased expression of alpha-smooth muscle actin and Ki-67 compared to untreated MSCs.
The study suggests that SA-EXOs are potent SASP factors that play a significant role in cancer-related fibrosis and that the miRNAs in these exosomes can play important roles in cell-cell communication during disease progression. Integrative pathway analysis revealed that radiation-induced senescence significantly enriched cell-cycle, extracellular matrix, TGF-β signalling, and vesicle-mediated transport genes in MSCs.
Radiation-induced fibrosis is a common side effect of radiotherapy, the most common cancer treatment. However, radiation also causes the development of senescence in normal cells that reside in irradiated tissues, which remain metabolically active but develop a potent senescence-associated secretory phenotype (SASP). This phenotype is characterized by hyperactive secretion of cytokines, pro-fibrotic growth factors, and exosomes (EXOs).
EXOs are nanovesicles secreted by cells that contain biomaterials critical in cell-cell communication, such as proteins, RNAs, and microRNAs (miRNAs). The miRNA content analysis of secreted EXOs revealed that radiation-induced senescence uniquely alters miRNA profiles. In fact, several of the standout miRNAs directly targeted TGF-β or downstream genes.
The findings of this study provide important insights into the mechanisms of radiation-induced fibrosis and the potential role of SA-EXOs in cancer-related fibrosis. Further research in this area could lead to the development of new therapeutic strategies to target SA-EXOs and prevent or treat cancer-related fibrosis.