免疫微环境对肿瘤干细胞影响研究进展
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摘要
肿瘤干细胞是肿瘤组织中一小群特殊的未分化的细胞,由于其对化疗药耐受及致瘤潜能,被认为是造成肿瘤发生、复发和转移的根源,所以深入了解肿瘤干细胞特性对提高肿瘤治疗效率有着重要临床意义.肿瘤微环境中的免疫细胞及其分泌的分子与肿瘤干细胞之间存在复杂的相互作用,可以维持肿瘤干细胞的干性及自我更新能力.目前,肿瘤免疫微环境对肿瘤干细胞的影响、肿瘤干细胞对免疫微环境的塑造作用以及靶向肿瘤干细胞或免疫微环境等研究,是肿瘤干细胞研究领域的热点问题.本文就免疫微环境对肿瘤干细胞的影响、靶向肿瘤干细胞及微环境治疗的研究进展进行了综述.
Cancer stem cells(CSCs) are a small group of special undifferentiated cells in tumor tissues. Because of the drug tolerance and tumorigenic potential, CSCs are considered to be the source of tumor occurrence,recurrence and metastasis. Therefore, it is very significant to understand the characteristics of CSCs in augmenting clinical therapeutic efficiency. In tumor microenvironment the complex crosstalk between immune cells and CSCs sustains the stemness and self-renewal ability of CSCs. The effect of immune microenvironment on CSCs, the role of CSCs in shaping immune microenvironment, and the targeted therapy of CSCs or immune microenvironment are hot topics in this field. In this review, the effects of immune microenvironment on the characteristics of CSCs and the research progress of targeting CSCs and microenvironment are summarized.
Cancer stem cells(CSCs) are a small group of special undifferentiated cells in tumor tissues. Because of the drug tolerance and tumorigenic potential, CSCs are considered to be the source of tumor occurrence,recurrence and metastasis. Therefore, it is very significant to understand the characteristics of CSCs in augmenting clinical therapeutic efficiency. In tumor microenvironment the complex crosstalk between immune cells and CSCs sustains the stemness and self-renewal ability of CSCs. The effect of immune microenvironment on CSCs, the role of CSCs in shaping immune microenvironment, and the targeted therapy of CSCs or immune microenvironment are hot topics in this field. In this review, the effects of immune microenvironment on the characteristics of CSCs and the research progress of targeting CSCs and microenvironment are summarized.
引文
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[5]Schurch C M,Riether C,Ochsenbein A F.Cytotoxic CD8+T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells.Cell Stem Cell,2014,14(4):460-472
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[12]Joshi P,Kooshki M,Aldrich W,et al.Expression of natural killer cell regulatory microRNA by uveal melanoma cancer stem cells.Clin Exp Metastasis,2016,33(8):829-838
[13]Ferreira-Teixeira M,Paiva-Oliveira D,Parada B,et al.Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells.BMC Med,2016,14(1):163
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[15]Zhao D,Pan C,Sun J,et al.VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2.Oncogene,2015,34(24):3107-3119
[16]Tirino V,Camerlingo R,Bifulco K,et al.TGF-beta1 exposure induces epithelial to mesenchymal transition both in CSCs and non-CSCs of the A549 cell line,leading to an increase of migration ability in the CD133+A549 cell fraction.Cell Death Dis,2013,4:e620
[17]Wang Y,Jiang M,Li Z,et al.Hypoxia and TGF-beta1 lead to endostatin resistance by cooperatively increasing cancer stem cells inA549 transplantation tumors.Cell Biosci,2015,5:72
[18]Voo K S,Wang Y H,Santori F R,et al.Identification of IL-17-producing FOXP3+regulatory T cells in humans.Proc Natl Acad Sci USA,2009,106(12):4793-4798
[19]Yang S,Wang B,Guan C,et al.Foxp3+IL-17+T cells promote development of cancer-initiating cells in colorectal cancer.JLeukoc Biol,2011,89(1):85-91
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[22]He K F,Zhang L,Huang C F,et al.CD163+tumor-associated macrophages correlated with poor prognosis and cancer stem cells in oral squamous cell carcinoma.Biomed Res Int,2014,2014:838632
[23]Chen Y,Tan W,Wang C.Tumor-associated macrophage-derived cytokines enhance cancer stem-like characteristics through epithelial-mesenchymal transition.Onco Targets Ther,2018,11:3817-3826
[24]Zeng J,Liu Z,Sun S,et al.Tumor-associated macrophages recruited by periostin in intrahepatic cholangiocarcinoma stem cells.Oncol Lett,2018,15(6):8681-8686
[25]Jinushi M,Chiba S,Yoshiyama H,et al.Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells.Proc Natl Acad Sci USA,2011,108(30):12425-12430
[26]Yang J,Liao D,Chen C,et al.Tumor‐associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox‐2 signaling pathway.Stem cells,2013,31(2):248-258
[27]Wan S,Zhao E,Kryczek I,et al.Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells.Gastroenterology,2014,147(6):1393-1404
[28]Fan Q M,Jing Y Y,Yu G F,et al.Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma.Cancer Lett,2014,352(2):160-168
[29]Zhang X,Zhang Y,Xu J,et al.Antigen presentation of the Oct4 and Sox2 peptides by CD154-activated B lymphocytes enhances the killing effect of cytotoxic T lymphocytes on tumor stem-like cells derived from cisplatin-resistant lung cancer cells.J Cancer,2018,9(2):367-374
[30]Xu L,Wang X,Wang J,et al.Hypoxia-induced secretion of IL-10from adipose-derived mesenchymal stem cell promotes growth and cancer stem cell properties of Burkitt lymphoma.Tumor Biology,2016,37(6):7835-7842
[31]Grange C,Tapparo M,Tritta S,et al.Role of HLA-G and extracellular vesicles in renal cancer stem cell-induced inhibition of dendritic cell differentiation.BMC Cancer,2015,15:1009
[32]Szarynska M,Olejniczak A,Kobiela J,et al.Cancer stem cells as targets for DC-based immunotherapy of colorectal cancer.Sci Rep,2018,8(1):12042
[33]Ramutton T,Buccheri S,Dieli F,et al.gammadelta T cells as a potential tool in colon cancer immunotherapy.Immunotherapy,2014,6(9):989-999
[34]Todaro M,Perez Alea M,Scopelliti A,et al.IL-4-mediated drug resistance in colon cancer stem cells.Cell Cycle,2008,7(3):309-313
[35]Hanash A M,Dudakov J A,Hua G,et al.Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease.Immunity,2012,37(2):339-350
[36]Kryczek I,Lin Y,Nagarsheth N,et al.IL-22(+)CD4(+)T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L.Immunity,2014,40(5):772-784
[37]Cui T X,Kryczek I,Zhao L,et al.Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101and suppressing the corepressor CtBP2.Immunity,2013,39(3):611-621
[38]Peng D,Tanikawa T,Li W,et al.Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling.Cancer Res,2016,76(11):3156-3165
[39]Sun L,Wang Q,Chen B,et al.Human gastric cancer mesenchymal stem cell-derived IL15 contributes to tumor cell epithelialmesenchymal transition via upregulation Tregs ratio and PD-1expression in CD4(+)T cell.Stem Cells Dev,2018,27(17):1203-1214
[40]Milanovic M,Fan D N Y,Belenki D,et al.Senescence-associated reprogramming promotes cancer stemness.Nature,2018,553(7686):96-100
[41]Chen D,Wu M,Li Y,et al.Targeting BMI1(+)cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma.Cell Stem Cell,2017,20(5):621-634.e6
[42]Chen J,Li J,Wu L,et al.Syntheses and anti-pancreatic cancer activities of rakicidin A analogues.Eur J Med Chem,2018,151:601-627
[43]Sun Y,Ding Y,Li D,et al.Cyclic depsipeptide BE-43547A2:synthesis and activity against pancreatic cancer stem cells.Angew Chem Int Ed Engl,2017,56(46):14627-14631
[44]Wang J,Kuang B,Guo X,et al.Total syntheses and biological activities of vinylamycin analogues.J Med Chem,2017,60(3):1189-1209
[45]Kumar V,Donthireddy L,Marvel D,et al.Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors.Cancer Cell,2017,32(5):654-668 e655
[46]Dianat-Moghadam H,Rokni M,Marofi F,et al.Natural killer cellbased immunotherapy:from transplantation toward targeting cancer stem cells.J Cell Physiol,2018,234(1):259-273
[47]Zhu X,Prasad S,Gaedicke S,et al.Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57.Oncotarget,2015,6(1):171-184
[48]Han J,Chu J,Keung Chan W,et al.CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells.Sci Rep,2015,5:11483
[49]Zhou B B,Zhang H,Damelin M,et al.Tumour-initiating cells:challenges and opportunities for anticancer drug discovery.Nat Rev Drug Discov,2009,8(10):806-823
[50]Baumann M,Krause M,Hill R.Exploring the role of cancer stem cells in radioresistance.Nat Rev Cancer,2008,8(7):545-554
[51]Sui Q,Zhang J,Sun X,et al.NK cells are the crucial antitumor mediators when STAT3-mediated immunosuppression is blocked in hepatocellular carcinoma.J Immunol,2014,193(4):2016-2023
[52]Sun X,Sui Q,Zhang C,et al.Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression.Mol Cancer Ther,2013,12(12):2885-2896
[53]Almiron Bonnin D A,Havrda M C,Lee M C,et al.Secretionmediated STAT3 activation promotes self-renewal of glioma stemlike cells during hypoxia.Oncogene,2018,37(8):1107-1118
[54]Yang Z,He L,Lin K,et al.The KMT1A-GATA3-STAT3 circuit is a novel self-renewal signaling of human bladder cancer stem cells.Clin Cancer Res,2017,23(21):6673-6685
[55]Lee T K,Castilho A,Cheung V C,et al.CD24(+)liver tumorinitiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation.Cell Stem Cell,2011,9(1):50-63
[56]Wang X,Li Y,Dai Y,et al.Sulforaphane improves chemotherapy efficacy by targeting cancer stem cell-like properties via the miR-124/IL-6R/STAT3 axis.Sci Rep,2016,6:36796
[57]Luo Y,Cui Y,Cao X,et al.8-Bromo-7-methoxychrysin-blocked STAT3/Twist axis inhibits the stemness of cancer stem cell-like cell originated from SMMC-7721 cells.Acta Biochim Biophys Sin(Shanghai),2017,49(5):458-464
[58]Kim Y J,Kim J Y,Lee N,et al.Disulfiram suppresses cancer stemlike properties and STAT3 signaling in triple-negative breast cancer cells.Biochem Biophys Res Commun,2017,486(4):1069-1076
[59]Li Y,Atkinson K,Zhang T.Combination of chemotherapy and cancer stem cell targeting agents:preclinical and clinical studies.Cancer Lett,2017,396:103-109
[60]Ning N,Pan Q,Zheng F,et al.Cancer stem cell vaccination confers significant antitumor immunity.Cancer Res,2012,72(7):1853-1864
[61]Lee Y,Sunwoo J.PD-L1 is preferentially expressed on CD44+tumor-initiating cells in head and neck squamous cell carcinoma.Journal for ImmunoTherapy of Cancer,2014,2(Suppl 3):P270
[62]Wang T,Narayanaswamy R,Ren H,et al.Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.Cancer Biol Ther,2016,17(6):698-707
[63]Schott A F,Landis M D,Dontu G,et al.Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors.Clin Cancer Res,2013,19(6):1512-1524
[2]Morrison B J,Steel J C,Morris J C.Reduction of MHC-Iexpression limits T-lymphocyte-mediated killing of cancerinitiating cells.BMC Cancer,2018,18(1):469
[3]Oh S J,Cho H,Kim S,et al.Targeting cyclin D-CDK4/6 sensitizes immune-refractory cancer by blocking the SCP3-NANOG axis.Cancer Res,2018,78(10):2638-2653
[4]Liu Y,Liang X,Yin X,et al.Blockade of IDO-kynurenine-AhRmetabolic circuitry abrogates IFN-gamma-induced immunologic dormancy of tumor-repopulating cells.Nat Commun,2017,8:15207
[5]Schurch C M,Riether C,Ochsenbein A F.Cytotoxic CD8+T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells.Cell Stem Cell,2014,14(4):460-472
[6]Liu Y,Liang X,Dong W,et al.Tumor-repopulating cells induce PD-1 expression in CD8(+)T cells by transferring kynurenine and AhR activation.Cancer Cell,2018,33(3):480-494.e7
[7]Avril T,Vauleon E,Hamlat A,et al.Human glioblastoma stem-like cells are more sensitive to allogeneic NK and T cell-mediated killing compared with serum-cultured glioblastoma cells.Brain Pathol,2012,22(2):159-174
[8]Tallerico R,Todaro M,Di Franco S,et al.Human NK cells selective targeting of colon cancer-initiating cells:a role for natural cytotoxicity receptors and MHC class I molecules.JImmunol,2013,190(5):2381-2390
[9]Kim G R,Ha G H,Bae J H,et al.Metastatic colon cancer cell populations contain more cancer stem-like cells with a higher susceptibility to natural killer cell-mediated lysis compared with primary colon cancer cells.Oncol Lett,2015,9(4):1641-1646
[10]Ames E,Canter R J,Grossenbacher S K,et al.NK cells preferentially target tumor cells with a cancer stem cell phenotype.J Immunol,2015,195(8):4010-4019
[11]Wang B,Wang Q,Wang Z,et al.Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells.Cancer Res,2014,74(20):5746-5757
[12]Joshi P,Kooshki M,Aldrich W,et al.Expression of natural killer cell regulatory microRNA by uveal melanoma cancer stem cells.Clin Exp Metastasis,2016,33(8):829-838
[13]Ferreira-Teixeira M,Paiva-Oliveira D,Parada B,et al.Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells.BMC Med,2016,14(1):163
[14]Pierini A,Alvarez M,Negrin R S.NK cell and CD4+FoxP3+regulatory T cell based therapies for hematopoietic stem cell engraftment.Stem Cells Int,2016,2016:9025835
[15]Zhao D,Pan C,Sun J,et al.VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2.Oncogene,2015,34(24):3107-3119
[16]Tirino V,Camerlingo R,Bifulco K,et al.TGF-beta1 exposure induces epithelial to mesenchymal transition both in CSCs and non-CSCs of the A549 cell line,leading to an increase of migration ability in the CD133+A549 cell fraction.Cell Death Dis,2013,4:e620
[17]Wang Y,Jiang M,Li Z,et al.Hypoxia and TGF-beta1 lead to endostatin resistance by cooperatively increasing cancer stem cells inA549 transplantation tumors.Cell Biosci,2015,5:72
[18]Voo K S,Wang Y H,Santori F R,et al.Identification of IL-17-producing FOXP3+regulatory T cells in humans.Proc Natl Acad Sci USA,2009,106(12):4793-4798
[19]Yang S,Wang B,Guan C,et al.Foxp3+IL-17+T cells promote development of cancer-initiating cells in colorectal cancer.JLeukoc Biol,2011,89(1):85-91
[20]Noy R,Pollard J W.Tumor-associated macrophages:from mechanisms to therapy.Immunity,2014,41(1):49-61
[21]Hou Y C,Chao Y J,Tung H L,et al.Coexpression of CD44-positive/CD133-positive cancer stem cells and CD204-positive tumor-associated macrophages is a predictor of survival in pancreatic ductal adenocarcinoma.Cancer,2014,120(17):2766-2777
[22]He K F,Zhang L,Huang C F,et al.CD163+tumor-associated macrophages correlated with poor prognosis and cancer stem cells in oral squamous cell carcinoma.Biomed Res Int,2014,2014:838632
[23]Chen Y,Tan W,Wang C.Tumor-associated macrophage-derived cytokines enhance cancer stem-like characteristics through epithelial-mesenchymal transition.Onco Targets Ther,2018,11:3817-3826
[24]Zeng J,Liu Z,Sun S,et al.Tumor-associated macrophages recruited by periostin in intrahepatic cholangiocarcinoma stem cells.Oncol Lett,2018,15(6):8681-8686
[25]Jinushi M,Chiba S,Yoshiyama H,et al.Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells.Proc Natl Acad Sci USA,2011,108(30):12425-12430
[26]Yang J,Liao D,Chen C,et al.Tumor‐associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox‐2 signaling pathway.Stem cells,2013,31(2):248-258
[27]Wan S,Zhao E,Kryczek I,et al.Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells.Gastroenterology,2014,147(6):1393-1404
[28]Fan Q M,Jing Y Y,Yu G F,et al.Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma.Cancer Lett,2014,352(2):160-168
[29]Zhang X,Zhang Y,Xu J,et al.Antigen presentation of the Oct4 and Sox2 peptides by CD154-activated B lymphocytes enhances the killing effect of cytotoxic T lymphocytes on tumor stem-like cells derived from cisplatin-resistant lung cancer cells.J Cancer,2018,9(2):367-374
[30]Xu L,Wang X,Wang J,et al.Hypoxia-induced secretion of IL-10from adipose-derived mesenchymal stem cell promotes growth and cancer stem cell properties of Burkitt lymphoma.Tumor Biology,2016,37(6):7835-7842
[31]Grange C,Tapparo M,Tritta S,et al.Role of HLA-G and extracellular vesicles in renal cancer stem cell-induced inhibition of dendritic cell differentiation.BMC Cancer,2015,15:1009
[32]Szarynska M,Olejniczak A,Kobiela J,et al.Cancer stem cells as targets for DC-based immunotherapy of colorectal cancer.Sci Rep,2018,8(1):12042
[33]Ramutton T,Buccheri S,Dieli F,et al.gammadelta T cells as a potential tool in colon cancer immunotherapy.Immunotherapy,2014,6(9):989-999
[34]Todaro M,Perez Alea M,Scopelliti A,et al.IL-4-mediated drug resistance in colon cancer stem cells.Cell Cycle,2008,7(3):309-313
[35]Hanash A M,Dudakov J A,Hua G,et al.Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease.Immunity,2012,37(2):339-350
[36]Kryczek I,Lin Y,Nagarsheth N,et al.IL-22(+)CD4(+)T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L.Immunity,2014,40(5):772-784
[37]Cui T X,Kryczek I,Zhao L,et al.Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101and suppressing the corepressor CtBP2.Immunity,2013,39(3):611-621
[38]Peng D,Tanikawa T,Li W,et al.Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling.Cancer Res,2016,76(11):3156-3165
[39]Sun L,Wang Q,Chen B,et al.Human gastric cancer mesenchymal stem cell-derived IL15 contributes to tumor cell epithelialmesenchymal transition via upregulation Tregs ratio and PD-1expression in CD4(+)T cell.Stem Cells Dev,2018,27(17):1203-1214
[40]Milanovic M,Fan D N Y,Belenki D,et al.Senescence-associated reprogramming promotes cancer stemness.Nature,2018,553(7686):96-100
[41]Chen D,Wu M,Li Y,et al.Targeting BMI1(+)cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma.Cell Stem Cell,2017,20(5):621-634.e6
[42]Chen J,Li J,Wu L,et al.Syntheses and anti-pancreatic cancer activities of rakicidin A analogues.Eur J Med Chem,2018,151:601-627
[43]Sun Y,Ding Y,Li D,et al.Cyclic depsipeptide BE-43547A2:synthesis and activity against pancreatic cancer stem cells.Angew Chem Int Ed Engl,2017,56(46):14627-14631
[44]Wang J,Kuang B,Guo X,et al.Total syntheses and biological activities of vinylamycin analogues.J Med Chem,2017,60(3):1189-1209
[45]Kumar V,Donthireddy L,Marvel D,et al.Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors.Cancer Cell,2017,32(5):654-668 e655
[46]Dianat-Moghadam H,Rokni M,Marofi F,et al.Natural killer cellbased immunotherapy:from transplantation toward targeting cancer stem cells.J Cell Physiol,2018,234(1):259-273
[47]Zhu X,Prasad S,Gaedicke S,et al.Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57.Oncotarget,2015,6(1):171-184
[48]Han J,Chu J,Keung Chan W,et al.CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells.Sci Rep,2015,5:11483
[49]Zhou B B,Zhang H,Damelin M,et al.Tumour-initiating cells:challenges and opportunities for anticancer drug discovery.Nat Rev Drug Discov,2009,8(10):806-823
[50]Baumann M,Krause M,Hill R.Exploring the role of cancer stem cells in radioresistance.Nat Rev Cancer,2008,8(7):545-554
[51]Sui Q,Zhang J,Sun X,et al.NK cells are the crucial antitumor mediators when STAT3-mediated immunosuppression is blocked in hepatocellular carcinoma.J Immunol,2014,193(4):2016-2023
[52]Sun X,Sui Q,Zhang C,et al.Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression.Mol Cancer Ther,2013,12(12):2885-2896
[53]Almiron Bonnin D A,Havrda M C,Lee M C,et al.Secretionmediated STAT3 activation promotes self-renewal of glioma stemlike cells during hypoxia.Oncogene,2018,37(8):1107-1118
[54]Yang Z,He L,Lin K,et al.The KMT1A-GATA3-STAT3 circuit is a novel self-renewal signaling of human bladder cancer stem cells.Clin Cancer Res,2017,23(21):6673-6685
[55]Lee T K,Castilho A,Cheung V C,et al.CD24(+)liver tumorinitiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation.Cell Stem Cell,2011,9(1):50-63
[56]Wang X,Li Y,Dai Y,et al.Sulforaphane improves chemotherapy efficacy by targeting cancer stem cell-like properties via the miR-124/IL-6R/STAT3 axis.Sci Rep,2016,6:36796
[57]Luo Y,Cui Y,Cao X,et al.8-Bromo-7-methoxychrysin-blocked STAT3/Twist axis inhibits the stemness of cancer stem cell-like cell originated from SMMC-7721 cells.Acta Biochim Biophys Sin(Shanghai),2017,49(5):458-464
[58]Kim Y J,Kim J Y,Lee N,et al.Disulfiram suppresses cancer stemlike properties and STAT3 signaling in triple-negative breast cancer cells.Biochem Biophys Res Commun,2017,486(4):1069-1076
[59]Li Y,Atkinson K,Zhang T.Combination of chemotherapy and cancer stem cell targeting agents:preclinical and clinical studies.Cancer Lett,2017,396:103-109
[60]Ning N,Pan Q,Zheng F,et al.Cancer stem cell vaccination confers significant antitumor immunity.Cancer Res,2012,72(7):1853-1864
[61]Lee Y,Sunwoo J.PD-L1 is preferentially expressed on CD44+tumor-initiating cells in head and neck squamous cell carcinoma.Journal for ImmunoTherapy of Cancer,2014,2(Suppl 3):P270
[62]Wang T,Narayanaswamy R,Ren H,et al.Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.Cancer Biol Ther,2016,17(6):698-707
[63]Schott A F,Landis M D,Dontu G,et al.Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors.Clin Cancer Res,2013,19(6):1512-1524