Abstract
Cancer-associated fibroblasts (CAFs) are one of the most prominent cell types in the stromal compartment of the tumor microenvironment. CAFs support multiple aspects of cancer progression, including tumor initiation, invasion, and metastasis. The heterogeneous nature of the stromal microenvironment is attributed to the multiple sources from which the cells in this compartment originate. The present study provides the first evidence that cancer stem cells (CSCs) are one of the key sources of CAFs in the tumor niche. We generated CSC-like cells by treating mouse induced pluripotent stem cells with conditioned medium from breast cancer cell lines. The resulting cell population expressed both CSC and pluripotency markers, and the sphere-forming CSC-like cells formed subcutaneous tumors in nude mice. Intriguingly, these CSC-like cells always formed heterogeneous populations surrounded by myofibroblast-like cells. Based on this observation, we hypothesized that CSCs could be the source of the CAFs that support tumor maintenance and survival. To address this hypothesis, we induced the differentiation of spheres and purified the myofibroblast-like cells. The resulting cells exhibited a CAF-like phenotype, suggesting that they had differentiated into the subpopulations of cells that support CSC self-renewal. These findings provide novel insights into the dynamic interplay between various microenvironmental factors and CAFs in the CSC niche.
Highlights
Cancer-associated fibroblasts (CAFs) are one of the most prominent cell types in the stromal compartment of the tumor microenvironment
Conditioned medium was generated from two different breast cancer cell lines, T47D and BT549; respective culture medium was collected in 5% serum condition according to the previously established protocol[6]
The key cancer stem cells (CSCs) marker CD133 and the epithelial carcinoma marker EpCam were expressed at levels 3- to 10-fold higher in conditioned medium (CM)-T47D and CM-BT549 cells compared with untreated mouse induced pluripotent stem (miPS) cells
Summary
Cancer-associated fibroblasts (CAFs) are one of the most prominent cell types in the stromal compartment of the tumor microenvironment. Recent studies suggest that several types of stromal cells in the CSC niche play pivotal roles in maintaining the small population of CSCs responsible for cancer recurrence and drug resistance[4] It is unclear if CSCs directly support tumor maintenance and survival by generating CAFs. there is evidence to support the hypothesis that CAF-mediated paracrine signaling preserves the stemness of patient-derived primary CSCs over time[5], this hypothesis has yet to be confirmed. Our group recently developed a unique CSC model from mouse induced pluripotent stem (miPS) cells cultured with cancer cell-conditioned medium that mimicked the conditions of the tumor niche[6] Using this model, we found that CSCs gave rise to vascular endothelial-like cells, thereby creating a niche that maintained the balance between self-renewal and differentiation, and supported the growth of heterogeneous tumors[7]. Our in vitro CSC model system provides a unique tool for analyzing the role of CAFs derived from CSC-like cells in the tumor microenvironment
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