Adipose stem cell crosstalk with chemo-residual breast cancer cells: implications for tumor recurrence

Abstract

PurposeMost triple-negative breast cancer (TNBC) patients exhibit an incomplete response to neoadjuvant chemotherapy, resulting in chemo-residual tumor cells that drive tumor recurrence and patient mortality. Accordingly, strategies for eliminating chemo-residual tumor cells are urgently needed. Although stromal cells contribute to tumor cell invasion, to date, their ability to influence chemo-residual tumor cell behavior has not been examined. Our study is the first to investigate cross-talk between adipose-derived stem cells (ASCs) and chemo-residual TNBC cells. We examine if ASCs promote chemo-residual tumor cell proliferation, having implications for tumor recurrence.MethodsASC migration toward chemo-residual TNBC cells was tested in a transwell migration assay. Importance of the SDF-1α/CXCR4 axis was determined using neutralizing antibodies and a small molecule inhibitor. The ability of ASCs to drive tumor cell proliferation was analyzed by culturing tumor cells ± ASC conditioned media (CM) and determining cell counts. Downstream signaling pathways activated in chemo-residual tumor cells following their exposure to ASC CM were studied by immunoblotting. Importance of FGF2 in promoting proliferation was assessed using an FGF2-neutralizing antibody.ResultsASCs migrated toward chemo-residual TNBC cells in a CXCR4/SDF-1α-dependent manner. Moreover, ASC CM increased chemo-residual tumor cell proliferation and activity of extracellular signal-regulated kinase (ERK). An FGF2-neutralizing antibody inhibited ASC-induced chemo-residual tumor cell proliferation.ConclusionsASCs migrate toward chemo-residual TNBC cells via SDF-1α/CXCR4 signaling, and drive chemo-residual tumor cell proliferation in a paracrine manner by secreting FGF2 and activating ERK. This paracrine signaling can potentially be targeted to prevent tumor recurrence.

The Importance of Breast Adipose Tissue in Breast Cancer

“…A study by Park et al, 2013, shows that endotrophin secreted by adipose tissue confers resistance to cisplatin in BC mouse models [ 266 ]. Lyes et al, 2019, showed that ADSC secretes FGF2 which activates ERK signaling, thereby promoting the proliferation of chemotherapy residual TNBC cells through the SDF-1α/CXCR4 signaling pathway [ 267 ]. Furthermore, Yeh et al, 2017, showed that ADSC promotes doxorubicin resistance in TNBC by CXCL1 secretion, which upregulates the expression of ABCG2, an ATP binding cassette (ABC) transporter [ 268 ] responsible for multidrug resistance in cancers [ 269 ].…”

Adipose tissue-derived stem cells in breast reconstruction: a brief review on biology and translation

“…ADSCs can also upregulate the epithelial-mesenchymal transition markers of breast cancer cells, such as fibronectin, alpha smooth muscle actin, and vimentin, and promote the ability of tumor metastasis and invasion [ 89 , 92 , 93 ]. Through paracrine manner by secreting FGF-2 and activating extracellular signal-regulated kinase (ERK), ADSCs could drive tumor cell proliferation at the chemo-residual triple-negative breast cancer [ 94 ]. ADSCs might even fuse with tumor cells to form hybrid cells which possessed stronger proliferation and metastasis capabilities [ 95 ].…”

ADSCs stimulated by resistin promote breast cancer cell malignancy via CXCL5 in a breast cancer coculture model

“…In addition, breast cancer cells treated with the conditioned medium from human adipose tissue-derived macrophages exhibited enhanced malignant phenotypes, and these macrophages over-expressed a cluster of cancer-associated genes, with the C-X-C chemokine ligand 1 (CXCL1) and C-X-C chemokine ligand 5 (CXCL5) being mostly upregulated 18 . Moreover, dysregulation of adipose tissue-derived stem cells (ADSCs) has been associated with breast cancer progression and metastasis, possibly via the expression of multiple C-X-C chemokines 19 – 21 . As these adipose tissue-derived cells may have crucial roles in promoting breast malignancy by interacting with cancer cells in the breast tumor microenvironment, identifying and targeting their pathogenic molecular pathways have emerged as a potential strategy for breast cancer treatment 22 , 23 .…”