Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells.
Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells.
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DOI：
10.1007/s00262-008-0623-1
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发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Ioannides CG
中科院分区：
文献类型：
--
作者：
Mine T;Matsueda S;Li Y;Tokumitsu H;Gao H;Danes C;Wong KK;Wang X;Ferrone S;Ioannides CG
癌症干细胞（CSC）对化疗和放疗具有抗性。为了消除具有CSC样表型标志物的细胞，我们表征了：（1）在对吉西他滨（GEM）、紫杉醇（PTX）和5-氟尿嘧啶（5-FU）耐药的乳腺（MCF 7）和卵巢（SK-0 V-3）细胞中CD 44、CD 24、CD 133和MIC-A/B（NKG 2受体）的表达，以及（2）它们被NumB-和Notch-肽激活的CTL消除。在所有群体中，具有管腔CSC表型[上皮特异性抗原+（ESA）CD 44 hi CD 24 lo、CD 44 hi CD 133+和CD 133 + CD 24 lo]的细胞数量在耐药MCF 7和SK-0 V-3细胞中增加。同样，与药物敏感细胞相比，耐药肿瘤细胞中表达MIC-A/B的细胞数量增加了4倍。GEMRes MCF 7细胞具有比GEMSens MCF 7更低水平的Notch-1-胞外结构域（NECD）和Notch跨膜胞内结构域（TMIC）。Numb和Numb-L-[P]-Ser 265的水平在GEMRes和GEMSens MCF 7细胞中相似。只有Numb-L（长）-Ser 295的水平略有下降。这一发现表明，Notch-1切割成TMIC在GEMRes MCF 7细胞中受到抑制。由天然免疫原性肽Notch-1（2112−2120）和Numb-1（87−95）激活的PBMC消除了NICD阳性的CD 24 hi CD 24 lo MCF 7细胞。MCF 7细胞中的免疫原性Numb-1肽可能来源于Numb，[P]被未知激酶活化，因为星形孢菌素而不是渥曼青霉素和MAPK抑制剂降低了肽呈递。Numb和Notch是相互降解以分别停止和激活细胞增殖的拮抗蛋白。它们的肽被交替地呈递。靶向这两种拮抗蛋白应该有助于预防肿瘤对常规治疗有抗性的患者的转移。
Cancer stem cells (CSC) are resistant to chemoand 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-Xuorouracil (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.
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作者：
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DOI：
10.1073/pnas.0711613105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Liu, Suling;Ginestier, Christophe;Wicha, Max S.
通讯作者：
Wicha, Max S.