乳腺癌-基质相互作用:脂肪诱导的基质/干细胞年龄和癌症亚型介导的重塑。

IF 2.5 3区 医学 Q3 CELL & TISSUE ENGINEERING
Stem cells and development Pub Date : 2022-10-01 Epub Date: 2022-07-12 DOI:10.1089/scd.2021.0279
Katie M Hamel, Connor T King, Maryn B Cavalier, Kara Q Liimatta, Grace L Rozanski, Timothy A King, Meggie Lam, Grace C Bingham, C Ethan Byrne, Diensn Xing, Bridgette M Collins-Burow, Matthew E Burow, Jorge A Belgodere, Melyssa R Bratton, Bruce A Bunnell, Elizabeth C Martin
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引用次数: 0

摘要

脂肪组织的特征是作为激素和旁分泌因子来源的内分泌器官。在癌症等疾病中,来自脂肪组织的内分泌和旁分泌信号有助于癌症的进展。患有雌激素受体α阳性(ER-α+)乳腺癌症(BC)的年轻人对内分泌疗法的抵抗力增加,这表明这些细胞内的替代雌激素信号被激活。尽管如此,间质年龄对BC内分泌反应的影响尚不明确。为了确定年轻和老年ER-α+乳腺肿瘤之间的差异,从癌症基因组图谱中获得RNA测序数据。分析显示,与老年(≥65岁)肿瘤样本相比,年轻(≤40岁)患者的基质和旁分泌因子富集。评估来自年轻和老年供体的非癌性脂肪抽吸物的脂肪来源的基质/干细胞(ASCs)的基质产生和旁分泌因子的变化,以确定肿瘤基质是否可以改变雌激素信号。年轻和老年ASCs表现出相似的增殖、分化和基质产生,但在炎性细胞因子(干扰素γ、白细胞介素[8、IL-10、肿瘤坏死因子α、IL-2和IL-6)的表达水平上存在差异。基于条件培养基(CM)的实验表明,年轻的ASC供体年龄提高了ER-α+BC细胞系的内分泌反应。与用老化ASC CM处理的MCF-7细胞相比,用年轻ASC分泌因子处理的MCF-7 ER-α+BC细胞系具有增强的ER-α调节基因(PGR和SDF-1)。蛋白质印迹分析表明,用年轻ASC-分泌因子处理MCF-7系中p-ER-ser-167的激活水平增加。为了确定ER-α+BC细胞是否增加ASCs中细胞因子的释放,用MCF-7衍生的CM刺激ASCs。结果表明,用ER-α+分泌组处理时,生长因子或细胞因子没有变化。与ER-α+CM相比,ER-α阴性MDA-MB-231衍生的CM对ASCs中促炎细胞因子的刺激增加。虽然没有观察到所选旁分泌因子的释放发生变化,但MCF-7细胞确实诱导了基质的产生和促脂肪谱系的承诺。天狼星红/快绿胶原染色显示胶原含量增加,油红O染色显示脂质积聚明显,PPARγmRNA表达显著增加,可见脂肪生成。这项研究的数据提供了证据,表明基质对BC的反应更多地是亚型依赖性的,而不是年龄依赖性的差异,这表明ER-α+BC细胞系的相互信号不会增强这种信号传导。这些结果对于理解雌激素信号传导的机制以及癌症细胞-基质细胞串扰的动态和相互性质是重要的,这些串扰可能导致肿瘤异质性和对治疗的反应变化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Breast Cancer-Stromal Interactions: Adipose-Derived Stromal/Stem Cell Age and Cancer Subtype Mediated Remodeling.

Adipose tissue is characterized as an endocrine organ that acts as a source of hormones and paracrine factors. In diseases such as cancer, endocrine and paracrine signals from adipose tissue contribute to cancer progression. Young individuals with estrogen receptor-alpha positive (ER-α+) breast cancer (BC) have an increased resistance to endocrine therapies, suggesting that alternative estrogen signaling is activated within these cells. Despite this, the effects of stromal age on the endocrine response in BC are not well defined. To identify differences between young and aged ER-α+ breast tumors, RNA sequencing data were obtained from The Cancer Genome Atlas. Analysis revealed enrichment of matrix and paracrine factors in young (≤40 years old) patients compared to aged (≥65 years old) tumor samples. Adipose-derived stromal/stem cells (ASCs) from noncancerous lipoaspirate of young and aged donors were evaluated for alterations in matrix production and paracrine secreted factors to determine if the tumor stroma could alter estrogen signaling. Young and aged ASCs demonstrated comparable proliferation, differentiation, and matrix production, but exhibited differences in the expression levels of inflammatory cytokines (Interferon gamma, interleukin [IL]-8, IL-10, Tumor necrosis factor alpha, IL-2, and IL-6). Conditioned media (CM)-based experiments showed that young ASC donor age elevated endocrine response in ER-α+ BC cell lines. MCF-7 ER-α+ BC cell line treated with secreted factors from young ASCs had enhanced ER-α regulated genes (PGR and SDF-1) compared to MCF-7 cells treated with aged ASC CM. Western blot analysis demonstrated increased activation levels of p-ER ser-167 in the MCF-7 cell line treated with young ASC secreted factors. To determine if ER-α+ BC cells heightened the cytokine release in ASCs, ASCs were stimulated with MCF-7-derived CM. Results demonstrated no change in growth factors or cytokines when treated with the ER-α+ secretome. In contrast to ER-α+ CM, the ER-α negative MDA-MB-231 derived CM demonstrated increased stimulation of pro-inflammatory cytokines in ASCs. While there was no observed change in the release of selected paracrine factors, MCF-7 cells did induce matrix production and a pro-adipogenic lineage commitment. The adipogenesis was evident by increased collagen content through Sirius Red/Fast Green Collagen stain, lipid accumulation evident by Oil Red O stain, and significantly increased expression in PPARγ mRNA expression. The data from this study provide evidence suggesting more of a subtype-dependent than an age-dependent difference in stromal response to BC, suggesting that this signaling is not heightened by reciprocal signals from ER-α+ BC cell lines. These results are important in understanding the mechanisms of estrogen signaling and the dynamic and reciprocal nature of cancer cell-stromal cell crosstalk that can lead to tumor heterogeneity and variance in response to therapy.

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来源期刊
Stem cells and development
Stem cells and development 医学-细胞与组织工程
CiteScore
7.80
自引率
2.50%
发文量
69
审稿时长
3 months
期刊介绍: Stem Cells and Development is globally recognized as the trusted source for critical, even controversial coverage of emerging hypotheses and novel findings. With a focus on stem cells of all tissue types and their potential therapeutic applications, the Journal provides clinical, basic, and translational scientists with cutting-edge research and findings. Stem Cells and Development coverage includes: Embryogenesis and adult counterparts of this process Physical processes linking stem cells, primary cell function, and structural development Hypotheses exploring the relationship between genotype and phenotype Development of vasculature, CNS, and other germ layer development and defects Pluripotentiality of embryonic and somatic stem cells The role of genetic and epigenetic factors in development
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