Breast cancer cells expressing stem cell markers CD44+ CD24lo are eliminated by Numb-1 peptide-activated T cells |
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| Authors: | 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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| Affiliation: | (1) Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA;(2) Departments of Immunology and Surgery, Kurume University School of Medicine, Kurume, Japan;(3) Department of Cell Signaling, Faculty of Medicine, Kagawa University, Kagawa, Japan;(4) Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA;(5) Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA;(6) Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA;(7) Departments of Surgery, Immunology and Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15123, USA;(8) Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA;(9) Multidisciplinary Treatment Center, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan |
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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. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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| Keywords: | Drug resistance Breast/ovarian Cancer stem cell Notch Numb Peptide |
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