Abstract
The roles of the tumor microenvironment (TME) in generating intra-tumoral diversity within each specific breast cancer subtype are far from being fully elucidated. In this study, we exposed Luminal-A breast cancer cells in culture to combined “TME Stimulation”, representing three typical arms of the breast TME: hormonal (estrogen), inflammatory (tumor necrosis factor α) and growth-promoting (epidermal growth factor). In addition to enriching the tumor cell population with CD44+/β1+ cells (as we previously published), TME Stimulation selected for CD44+/CD24low/− stem-like cells, that were further enriched by doxorubicin treatment and demonstrated high plasticity in vitro and in vivo. Knock-down experiments revealed that CD44 and Zeb1 regulated CD24 and β1 expression and controlled differently cell spreading and formation of cellular protrusions. TME-enriched CD44+/CD24low/− stem-like cells promoted dissemination to bones and lymph nodes, whereas CD44+/β1+ cells had a low metastatic potential. Mixed co-injections of TME-enriched CD44+/CD24low/− and CD44+/β1+ sub-populations generated metastases populated mostly by CD44+/CD24low/−-derived cells. Thus, combined activities of several TME factors select for CD44+/CD24low/− stem-like cells that dictate the metastatic phenotype of Luminal-A breast tumor cells, suggesting that therapeutic modalities targeting the TME could be introduced as a potential strategy of inhibiting the detrimental stem-like sub-population in this disease subtype.
Highlights
Many solid tumors are characterized by heterogeneity that impinges on tumor progression, prognosis and therapy
We determined the impact of tumor microenvironment (TME) Stimulation on the proportion of CD44+/CD24low/− cells and found that exposure to TME factors increased the proportion of the CD44+/CD24low/− sub-population in MCF-7 cells from 0.9±0.5% to 13.8 ± 6.9% (Figure 1A; Supplementary Figure S2A1), and in T47D cells from 0.3 ± 0.3% to 5.5 ± 2.1% (Figure 1B; Supplementary Figure S2A2) (The impact of TME Stimulation on the expression of CD24 alone in MCF-7 an T47D cells is demonstrated in Supplementary Figure S2B)
In response to TME Stimulation, two cell sub-populations were enriched in MCF-7 and T47D Luminal-A breast tumor cells: cells with the CD44+/β1+ phenotype and cells with the CD44+/CD24low/− phenotype, the latter possibly representing a sub-population of cancer stem cells (CSCs)
Summary
Many solid tumors are characterized by heterogeneity that impinges on tumor progression, prognosis and therapy. Inter-tumoral heterogeneity is typical of breast tumors and intra-tumoral heterogeneity that can dictate the metastatic potential of the cells and their resistance to therapy [5]. Such intratumoral heterogeneity is reflected by varying expression levels of defined markers within the same tumor [such as estrogen receptors (ER)] and by clonal genetic diversity within tumors [5,6,7]. The term CSCs reflects the potential of these cells to self-renew and reconstitute the entire tumor mass, with its phenotypic heterogeneity, when transplanted to mice [8, 9]. Increasing evidence indicates that the CSC sub-population is the one that initiates metastases and provides resistance to chemotherapy [10, 11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
