Microenvironmental networks promote tumor heterogeneity and enrich for metastatic cancer stem-like cells in Luminal-A breast tumor cells.
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.
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Polina
P
Weitzenfeld
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Tsipi
T
Meshel
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Adit
A
Ben-Baruch
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051927:CD24 Antigen / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D000066670:Cell Plasticity / Q000187:drug effects; D048430:Cell Shape; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D061986:MCF-7 Cells; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D004967:Estrogens; D018960:Hyaluronan Receptors; D019012:Integrin beta1; D014409:Tumor Necrosis Factor-alpha; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D004815:Epidermal Growth Factor
adhesion molecules; cancer stem cells; luminal-A breast cancer; metastasis; tumor microenvironment