Abstract
Triple-negative breast tumours (TNBTs) make up 15–20% of all breast tumours. There is no treatment for them, and the role that cancer stem cells (CSCs) have in carcinogenesis is still unclear, so finding markers and therapeutic targets in CSC exosomes requires these cells to exist as a homogeneous cell population. The objective of this work was to determine differences in ultrastructural morphology, proliferative capacity, and mouse-xenotransplantation characteristics of the MDA-MB-231 and MDA-MB-436 TNBT cell lines with the CD44high/CD24low phenotype in order to study their exosomes. The results show that the CD44high/CD24low MBA-MB-231 cells had a population doubling time of 41.56 h, compared to 44.79 h in the MDA-MB-436 cell line. After magnetic immunoseparation, 18.75% and 14.56% of the stem cell population of the MDA-MB-231 and MDA-MB-436 cell lines, respectively, were of the CD44high/CD24low phenotype, which were expanded to reach purities of 80.4% and 87.6%. The same expanded lineage in both cell lines was shown to possess the pluripotency markers Nanog and Oct4. Under a scanning electron microscope, the CD44high/CD24low lineage of the MBA-MD-231 cell line formed groups of more interconnected cells than this lineage of the MBA-MD-436 line. A total of 16% of the mice inoculated with the CD44high/CD24low lineage of either cell line presented tumours of the breast, lung, and submandibular ganglia, in whose tissues variable numbers of inoculated cells were found 30 days post-inoculation. By magnetic immunoselection, it was possible to isolate in similar quantities and characterize, expand, and xenotransplant the CD44high/CD24low lineage of the MDA-MB-231 and MDA-MB-436 cell lines. The former cell line has greater proliferative capacity, the two lines differ under scanning electron microscopy in how they intercommunicate, and both cell lines induce new tumours in mice and persist at least 30 days post-inoculation in the transplanted animal so their exosomes would also be different.
Highlights
Breast cancer includes very heterogeneous tumours, and a wide spectrum of factors are responsible for variations in therapeutic response and prognosis [1]
A better understanding of this biological heterogeneity will allow more effective and individualized treatment approaches [6]. As part of this effort, many researchers have focussed on cancer stem cells (CSCs), which have a greater tolerance to chemotherapy, hormonal therapy, and radiotherapy and are capable of reproducing the majority of the tumour after killing the populations of cells sensitive to first-line therapy, leading to relapse of the disease [7]
The objective of this study was to determine some biological differences not yet well described in a subpopulation of breast CSCs with the CD44high and CD24low immunophenotype of the MDA-MB 436 and MDA-MB-231 Triple-negative breast tumours (TNBTs) cell lines in order to obtain expanded and stable subpopulations that produced stable exosomes. These were homogeneous subpopulations in which we looked for differences in the content of markers and therapeutic targets in the CSCs of TNBTs
Summary
Breast cancer includes very heterogeneous tumours, and a wide spectrum of factors are responsible for variations in therapeutic response and prognosis [1]. A better understanding of this biological heterogeneity will allow more effective and individualized treatment approaches [6] As part of this effort, many researchers have focussed on cancer stem cells (CSCs), which have a greater tolerance to chemotherapy, hormonal therapy, and radiotherapy and are capable of reproducing the majority of the tumour after killing the populations of cells sensitive to first-line therapy, leading to relapse of the disease [7]. To identify these cancer stem cells, several new cell-surface markers of breast cancer associated with the CSC lineage have been discovered, such as the presence of CD44 (CD44high)
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