Original Article

Cancer Immunology, Immunotherapy

, Volume 58, Issue 8, pp 1185-1194

First online:

Breast cancer cells expressing stem cell markers CD44+ CD24lo are eliminated by Numb-1 peptide-activated T cells

  • Takashi MineAffiliated withDepartment of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer CenterDepartments of Immunology and Surgery, Kurume University School of MedicineMultidisciplinary Treatment Center, Kurume University School of Medicine Email author 
  • , Satoko MatsuedaAffiliated withDepartment of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
  • , Yufeng LiAffiliated withDepartment of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer CenterDepartment of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center
  • , Hiroshi TokumitsuAffiliated withDepartment of Cell Signaling, Faculty of Medicine, Kagawa University
  • , Hui GaoAffiliated withDepartment of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center
  • , Cristopher DanesAffiliated withDepartment of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center
  • , Kwong-Kwok WongAffiliated withDepartment of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
  • , Xinhui WangAffiliated withDepartments of Surgery, Immunology and Pathology, University of Pittsburgh Cancer Institute
  • , Soldano FerroneAffiliated withDepartments of Surgery, Immunology and Pathology, University of Pittsburgh Cancer Institute
    • , Constantin G. IoannidesAffiliated withDepartment of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer CenterDepartment of Immunology, The University of Texas M. D. Anderson Cancer Center

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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 GEMRes 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.

Keywords

Drug resistance Breast/ovarian Cancer stem cell Notch Numb Peptide