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Prolonged Drug Selection of Breast Cancer Cells and Enrichment of Cancer Stem Cell Characteristics

Calcagno, Anna Maria ; Salcido, Crystal D. ; Gillet, Jean-Pierre ; Wu, Chung-Pu ; Fostel, Jennifer M. ; Mumau, Melanie D. ; Gottesman, Michael M. ; Varticovski, Lyuba ; Ambudkar, Suresh V.

JNCI : Journal of the National Cancer Institute, 2010-11, Vol.102 (21), p.1637-1652 [Periódico revisado por pares]

Cary, NC: Oxford University Press

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Título:
Prolonged Drug Selection of Breast Cancer Cells and Enrichment of Cancer Stem Cell Characteristics
Autor: Calcagno, Anna Maria ; Salcido, Crystal D. ; Gillet, Jean-Pierre ; Wu, Chung-Pu ; Fostel, Jennifer M. ; Mumau, Melanie D. ; Gottesman, Michael M. ; Varticovski, Lyuba ; Ambudkar, Suresh V.
Assuntos: AC133 Antigen ; Animals ; Antibiotics, Antineoplastic - pharmacology ; Antigens, CD - metabolism ; Antineoplastic agents ; ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; Biological and medical sciences ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - pathology ; CD24 Antigen - metabolism ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Cell Survival ; Chemotherapy ; Collagen ; Confounding Factors (Epidemiology) ; Disease Models, Animal ; Doxorubicin - pharmacology ; Drug Combinations ; Drug resistance ; Drug Resistance, Multiple - genetics ; Drug Resistance, Neoplasm - genetics ; Female ; Flow Cytometry ; Gene Expression Regulation, Neoplastic ; General aspects ; Glycoproteins - metabolism ; Humans ; Hyaluronan Receptors - metabolism ; Laminin ; Lung Neoplasms - drug therapy ; Medical sciences ; Mice ; Mice, SCID ; Microarray Analysis ; Neoplastic Stem Cells - immunology ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Ovarian Neoplasms - drug therapy ; Peptides - metabolism ; Pharmacology. Drug treatments ; Proteoglycans ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - metabolism ; Stem cells ; Transplantation, Heterologous ; Tumors ; Up-Regulation ; Uterine Cervical Neoplasms - drug therapy
É parte de: JNCI : Journal of the National Cancer Institute, 2010-11, Vol.102 (21), p.1637-1652
Notas: ark:/67375/HXZ-B48SFM9B-6
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Descrição: Background Cancer stem cells are presumed to have virtually unlimited proliferative and self-renewal abilities and to be highly resistant to chemotherapy, a feature that is associated with overexpression of ATP-binding cassette transporters. We investigated whether prolonged continuous selection of cells for drug resistance enriches cultures for cancer stem–like cells. Methods Cancer stem cells were defined as CD44+/CD24− cells that could self-renew (ie, generate cells with the tumorigenic CD44+/CD24− phenotype), differentiate, invade, and form tumors in vivo. We used doxorubicin-selected MCF-7/ADR cells, weakly tumorigenic parental MCF-7 cells, and MCF-7/MDR, an MCF-7 subline with forced expression of ABCB1 protein. Cells were examined for cell surface markers and side-population fractions by microarray and flow cytometry, with in vitro invasion assays, and for ability to form mammospheres. Xenograft tumors were generated in mice to examine tumorigenicity (n = 52). The mRNA expression of multidrug resistance genes was examined in putative cancer stem cells and pathway analysis of statistically significantly differentially expressed genes was performed. All statistical tests were two-sided. Results Pathway analysis showed that MCF-7/ADR cells express mRNAs from ABCB1 and other genes also found in breast cancer stem cells (eg, CD44, TGFB1, and SNAI1). MCF-7/ADR cells were highly invasive, formed mammospheres, and were tumorigenic in mice. In contrast to parental MCF-7 cells, more than 30% of MCF-7/ADR cells had a CD44+/CD24− phenotype, could self-renew, and differentiate (ie, produce CD44+/CD24− and CD44+/CD24+ cells) and overexpressed various multidrug resistance–linked genes (including ABCB1, CCNE1, and MMP9). MCF-7/ADR cells were statistically significantly more invasive in Matrigel than parental MCF-7 cells (MCF-7 cells = 0.82 cell per field and MCF-7/ADR = 7.51 cells per field, difference = 6.69 cells per field, 95% confidence interval = 4.82 to 8.55 cells per field, P < .001). No enrichment in the CD44+/CD24− or CD133+ population was detected in MCF-7/MDR. Conclusion The cell population with cancer stem cell characteristics increased after prolonged continuous selection for doxorubicin resistance.
Editor: Cary, NC: Oxford University Press
Idioma: Inglês

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Prolonged Drug Selection of Breast Cancer Cells and Enrichment of Cancer Stem Cell Characteristics

Calcagno, Anna Maria ; Salcido, Crystal D. ; Gillet, Jean-Pierre ; Wu, Chung-Pu ; Fostel, Jennifer M. ; Mumau, Melanie D. ; Gottesman, Michael M. ; Varticovski, Lyuba ; Ambudkar, Suresh V.

Cary, NC: Oxford University Press

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