Oscillatory Hypoxia Can Induce Senescence of Adipose-Derived Mesenchymal Stromal Cells Potentiating Invasive Transformation of Breast Epithelial Cells

• Published in: Cancers Vol. 16; no. 5; p. 969
• Main Authors: Novin, Ashkan, Wali, Khadija, Pant, Aditya, Liu, Shaofei, Du, Wenqiang, Liu, Yamin, Wang, Lichao, Xu, Ming, Wang, Binsheng, Suhail, Yasir, Kshitiz
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.02.2024; MDPI
• Subjects: adipocyte-derived stromal cells; Adipocytes; Adipose tissue; Breast cancer; breast cancer dissemination; Cancer; Care and treatment; Cell migration; Chemotaxis; Development and progression; Epithelial cells; Epithelium; fluctuating hypoxia; Genes; Genotype & phenotype; Health aspects; Hypoxia; Invasiveness; Mesenchymal stem cells; Metastases; Metastasis; Microscopy; Obesity; oscillatory hypoxia; Oxygen consumption; Penicillin; Phenotypes; Potentiation; RNA; RNA sequencing; Senescence; Stem cells; Stromal cells; stromal invasion; Tumor cell lines; Tumor microenvironment; Tumors; United States > US; Fiji; adipocyte-derived stromal cells; MCF10A; stromal invasion; fluctuating hypoxia; oscillatory hypoxia; MSC recruitment; breast cancer; ASC; breast epithelial transformation; stromal dissemination; MCF10A1; tumor microenvironment; breast cancer dissemination
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16050969

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.