Obesity is strongly associated with occurrence, metastasis, and resistance to therapy in breast cancers, which also exhibit high adipose content in the tumor microenvironment. Adipose tissue-derived mesenchymal stromal cells (ASCs) are recruited to breast cancer by many mechanisms, including hypoxia, and contribute to metastatic transition of the cancer. Breast cancers are characterized by regions of hypoxia, which can be temporally unstable owing to a mismatch between oxygen supply and consumption. Using a high-sensitivity nanopatterned stromal invasion assay, we found that ASCs could promote stromal invasion of not only breast cancer cell lines but also MCF10A1, a cell line derived from untransformed breast epithelium. RNA sequencing of MCF10A1 cells conditioned with medium from ASCs revealed upregulation of genes associated with increased cell migration, chemotaxis, and metastasis. Furthermore, we found that fluctuating or oscillating hypoxia could induce senescence in ASCs, which could result in an increased invasive potential in the treated MCF10A1 cells. These findings highlight the complex interplay within the breast cancer microenvironment, hypoxia, and the role of ASCs in transforming even non-cancerous breast epithelium toward an invasive phenotype, providing insights into early metastatic events.
肥胖与乳腺癌的发生、转移及治疗抵抗密切相关，且乳腺癌肿瘤微环境中常含有大量脂肪组织。脂肪来源的间充质基质细胞（ASCs）可通过缺氧等多种机制被募集至乳腺癌组织，并促进癌症的转移进程。乳腺癌的特征之一是其内部存在缺氧区域，由于氧气供应与消耗之间的失衡，这种缺氧状态可能呈现时间不稳定性。通过高灵敏度纳米图案化基质侵袭实验，我们发现ASCs不仅能促进乳腺癌细胞系的基质侵袭，还能促进源自非转化乳腺上皮的MCF10A1细胞系的侵袭行为。对经ASCs条件培养基处理的MCF10A1细胞进行RNA测序分析，结果显示与细胞迁移、趋化性和转移相关的基因表达上调。此外，我们发现波动性或振荡性缺氧可诱导ASCs发生衰老，进而增强经处理的MCF10A1细胞的侵袭潜能。这些发现揭示了乳腺癌微环境与缺氧之间复杂的相互作用，阐明了ASCs在促使非癌性乳腺上皮向侵袭表型转化中的关键作用，为早期转移事件的研究提供了新的视角。
肿瘤(癌症)患者之家