Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
Plastic and Reconstructive Surgery Department, Metropolitan General Hospital, Athens, Greece.
IUBMB Life. 2022 Oct;74(10):969-981. doi: 10.1002/iub.2659. Epub 2022 Jul 14.
Radiotherapy is widely used for the treatment of breast cancer. However, we have shown that ionizing radiation can provoke premature senescence in breast stromal cells. In particular, breast stromal fibroblasts can become senescent after irradiation both in vitro and in vivo and they express an inflammatory phenotype and an altered profile of extracellular matrix components, thus facilitating tumor progression. Adipose-derived stem cells (ASCs) represent another major component of the breast tissue stroma. They are multipotent cells and due to their ability to differentiate in multiple cell lineages they play an important role in tissue maintenance and repair in normal and pathologic conditions. Here, we investigated the characteristics of human breast ASCs that became senescent prematurely after their exposure to ionizing radiation. We found decreased expression levels of the specific mesenchymal cell surface markers CD105, CD73, CD44, and CD90. In parallel, we demonstrated a significantly reduced expression of transcription factors regulating osteogenic (i.e., RUNX2), adipogenic (i.e., PPARγ), and chondrogenic (i.e., SOX9) differentiation; this was followed by an analogous reduction in their differentiation capacity. Furthermore, they overexpress inflammatory markers, that is, IL-6, IL-8, and ICAM-1, and a catabolic phenotype, marked by the reduction of collagen type I and the increase of MMP-1 and MMP-13 expression. Finally, we detected changes in proteoglycan expression, for example, the upregulation of syndecan 1 and syndecan 4 and the downregulation of decorin. Notably, all these alterations, when observed in the breast stroma, represent poor prognostic factors for tumor development. In conclusion, we showed that ionizing radiation-mediated prematurely senescent human breast ASCs have a decreased differentiation potential and express specific changes adding to the formation of a permissive environment for tumor growth.
放射疗法被广泛用于乳腺癌的治疗。然而，我们已经表明，电离辐射会导致乳腺基质细胞过早衰老。特别是，乳腺基质成纤维细胞在体外和体内照射后都可以衰老，并且它们表达炎症表型和细胞外基质成分的改变谱，从而促进肿瘤进展。脂肪来源的干细胞（ASCs）是乳腺组织基质的另一个主要成分。它们是多能细胞，由于其能够在多个细胞谱系中分化，因此在正常和病理条件下维持和修复组织中发挥重要作用。在这里，我们研究了暴露于电离辐射后过早衰老的人乳腺 ASC 的特征。我们发现特定的间充质细胞表面标志物 CD105、CD73、CD44 和 CD90 的表达水平降低。平行地，我们证明了调节成骨（即 RUNX2）、成脂（即 PPARγ）和软骨形成（即 SOX9）分化的转录因子的表达显著降低；随后，其分化能力也随之降低。此外，它们过度表达炎症标志物，即 IL-6、IL-8 和 ICAM-1，以及分解代谢表型，其特征是胶原蛋白 I 的减少和 MMP-1 和 MMP-13 的表达增加。最后，我们检测到蛋白聚糖表达的变化，例如，黏附素 1 和黏附素 4 的上调和饰胶蛋白的下调。值得注意的是，在乳腺基质中观察到的所有这些改变都代表肿瘤发展的预后不良因素。总之，我们表明，电离辐射介导的过早衰老的人乳腺 ASC 分化潜力降低，并表达特定的改变，这增加了有利于肿瘤生长的环境的形成。
