ABSTRACT
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.
Subject(s)
Core Binding Factor Alpha 1 Subunit , Syndecan-1 , Adipose Tissue/metabolism , Cell Differentiation/physiology , Cells, Cultured , Collagen Type I , Core Binding Factor Alpha 1 Subunit/metabolism , Decorin/metabolism , Extracellular Matrix/genetics , Humans , Intercellular Adhesion Molecule-1/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 13/metabolism , PPAR gamma/metabolism , Stem Cells/metabolism , Syndecan-1/metabolism , Syndecan-4/metabolismABSTRACT
OBJECTIVES: Pulmonary nocardiosis is an uncommon opportunistic infection affecting mainly immunocompromised patients. We herein present a case of nocardiosis without profound underlying immunodeficiency. BACKGROUND: A female, 84-years' old patient with stage IV chronic obstructive pulmonary disease (COPD) is presented. No profound causes of immunodeficiency existed, such as HIV infection, diabetes mellitus, malignancy, alcoholism, chemotherapy or previous corticosteroid intake. The patient recovered after treatment with trimethoprim/sulfamethoxazole for 6 months. RESULTS: One year after infection resolution, stimulation of the patient's blood monocytes with Nocardia antigens revealed defective production of tumor necrosis factor-alpha, interleukin (IL)-6 and IL-17. CONCLUSION: We provide preliminary evidence for a link between defective innate immune responses and predisposition for Nocardia infections. Further studies must be conducted in order to fully investigate this mechanism of infection acquisition.
