Abstract
Simple SummaryIonizing radiation (a typical remedy for breast cancer) results in the premature senescence of the adjacent to the neoplastic cells stromal fibroblasts. Here, we showed that these senescent fibroblasts are characterized by the down-regulation of the small leucine-rich proteoglycan decorin, a poor prognostic factor for the progression of the disease. Decorin down-regulation is mediated by secreted growth factors in an autocrine and paracrine (due to the interaction with breast cancer cells) manner, with bFGF and VEGF being the key players of this regulation in young and senescent breast stromal fibroblasts. Autophagy activation increases decorin mRNA levels, indicating that impaired autophagy is implicated in the reduction in decorin in this cell model. Decorin down-regulation acts additively to the already tumor-promoting phenotype of ionizing radiation-induced prematurely senescent human stromal fibroblasts, confirming that stromal senescence is a side-effect of radiotherapy that should be taken into account in the design of anticancer treatments.Down-regulation of the small leucine-rich proteoglycan decorin in the stroma is considered a poor prognostic factor for breast cancer progression. Ionizing radiation, an established treatment for breast cancer, provokes the premature senescence of the adjacent to the tumor stromal fibroblasts. Here, we showed that senescent human breast stromal fibroblasts are characterized by the down-regulation of decorin at the mRNA and protein level, as well as by its decreased deposition in the pericellular extracellular matrix in vitro. Senescence-associated decorin down-regulation is a long-lasting process rather than an immediate response to γ-irradiation. Growth factors were demonstrated to participate in an autocrine manner in decorin down-regulation, with bFGF and VEGF being the critical mediators of the phenomenon. Autophagy inhibition by chloroquine reduced decorin mRNA levels, while autophagy activation using the mTOR inhibitor rapamycin enhanced decorin transcription. Interestingly, the secretome from a series of both untreated and irradiated human breast cancer cell lines with different molecular profiles inhibited decorin expression in young and senescent stromal fibroblasts, which was annulled by SU5402, a bFGF and VEGF inhibitor. The novel phenotypic trait of senescent human breast stromal fibroblasts revealed here is added to their already described cancer-promoting role via the formation of a tumor-permissive environment.
Highlights
Cancer is one of the major causes of morbidity and mortality worldwide [1]
Decorin was found to be downregulated in ionizing radiation-induced senescent human breast stromal fibroblasts at the protein level (Figure 1C and Supplementary Figure S1)
We found that SU5402 led to the abrogation of decorin down-regulation induced by all growth factors tested (Figure 4A), corroborating the key role of basic FGF (bFGF) and vascular endothelial growth factor (VEGF) in modulating decorin expression in human breast stromal fibroblasts and suggesting that the action of platelet derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor (IGF)-I and transforming growth factor-β (TGF-β) is mediated by these two growth factors, most probably secondarily via an autocrine loop
Summary
Cancer is one of the major causes of morbidity and mortality worldwide [1]. Among the numerous different types of cancer, breast cancer is generally regarded as the most common malignancy, predominantly in female patients, and the second leading cause of cancer-related deaths in women around the world [1,2]. The stroma embracing cancer cells constitutes a high fraction of the solid tumor’s volume. It mainly consists of extracellular matrix (ECM) that encompasses the stromal cells, including fibroblasts, endothelial cells, specialized mesenchymal cells and immune cells [4]. The tumor microenvironment has emerged as a key participant in cancer progression via the modified synthesis and deposition of several ECM constituents and via its complex interactions with malignant cells [4,5,7,8,9]. A great number of studies have suggested that whereas a normal microenvironment can impede tumor growth, an activated stroma can be an accomplice in cancer development [10,11,12,13,14,15]
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