Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells

Takashi Mine, Satoko Matsueda, Yufeng Li, Hiroshi Tokumitsu, Hui Gao, Cristopher Danes, Kwong Kwok Wong, Xinhui Wang, Soldano Ferrone, Constantin G. Ioannides

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Abstract

Cancer stem cells (CSC) are resistant to chemo- and radiotherapy. To eliminate cells with phenotypic markers of CSC-like we characterized: (1) expression of CD44, CD24, CD133 and MIC-A/B (NKG2 receptors) in breast (MCF7) and ovarian (SK-OV-3) cells resistant to gemcitabine (GEM), paclitaxel (PTX) and 5-fluorouracil (5-FU) and (2) their elimination by Numb- and Notch-peptide activated CTL. The number of cells in all populations with the luminal CSC phenotype [epithelial specific antigen+ (ESA) CD44hi CD24lo, CD44hi CD133+, and CD133+ CD24lo] increased in drug-resistant MCF7 and SK-OV-3 cells. Similarly, the number of cells with expressed MIC-A/B increased 4 times in drug-resistant tumor cells compared with drug-sensitive cells. GEMRes MCF7 cells had lower levels of the Notch-1-extracellular domain (NECD) and Notch trans-membrane intracellular domain (TMIC) than GEMSens MCF7. The levels of Numb, and Numb-L-[P]-Ser265 were similar in GEM Res and GEMSens MCF7 cells. Only the levels of Numb-L (long)-Ser295 decreased slightly. This finding suggests that Notch-1 cleavage to TMIC is inhibited in GEMRes MCF7 cells. PBMC activated by natural immunogenic peptides Notch-1 (2112-2120) and Numb-1 (87-95) eliminated NICDpositive, CD24hi CD24lo MCF7 cells. It is likely that the immunogenic Numb-1 peptide in MCF7 cells originated from Numb, [P]-lated by an unknown kinase, because staurosporine but not wortmannin and MAPK-inhibitors decreased peptide presentation. Numb and Notch are antagonistic proteins which degrade each other to stop and activate cell proliferation, respectively. Their peptides are presented alternatively. Targeting both antagonistic proteins should be useful to prevent metastases in patients whose tumors are resistant to conventional treatments.

Original languageEnglish
Pages (from-to)1185-1194
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume58
Issue number8
DOIs
Publication statusPublished - Aug 2009
Externally publishedYes

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Keywords

  • Breast/ovarian
  • Cancer stem cell
  • Drug resistance
  • Notch
  • Numb
  • Peptide

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

Cite this

Mine, T., Matsueda, S., Li, Y., Tokumitsu, H., Gao, H., Danes, C., Wong, K. K., Wang, X., Ferrone, S., & Ioannides, C. G. (2009). Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells. Cancer Immunology, Immunotherapy, 58(8), 1185-1194. https://doi.org/10.1007/s00262-008-0623-1