肿瘤干细胞及靶向抗肿瘤新药
——攻克癌症的希望

doi:10.3969/j.issn.1004-616x.2014.04.015

摘要/Abstract

摘要：

目前，恶性肿瘤仍然是威胁人类健康且难以治愈的重大疾病。多年来相关的医药学家们对恶性肿瘤的发生、发展及防治不断地进行着探索。随着时间的推移，肿瘤的治疗手段从手术、放疗、化疗以及生物药物治疗等发展到靶向药物。但由于耐药产生快，对于肿瘤的转移与复发基本仍是束手无策。肿瘤转移与复发使得治疗变得极其困难与复杂，摆在医药学家们面前迫在眉睫思考的问题是：导致肿瘤复发的根源是什么？近年来，针对肿瘤细胞转移复发，发现肿瘤细胞生长、转移和复发的特点与干细胞的基本特征十分相似，针对肿瘤细胞的自我更新能力、不定潜能的异质性及少数肿瘤细胞的强致瘤性、高侵袭性及转移等，科学家提出了肿瘤干细胞的新概念，为治疗肿瘤提出了新思路。本文综述了肿瘤干细胞的起源、生物学特性、与肿瘤的关系及靶向抗肿瘤药物的研究进展。

关键词: 干细胞, 肿瘤干细胞, 自我更新, 异质性, 致瘤性, 靶向药物

王敬泽，李桂娟. 肿瘤干细胞及靶向抗肿瘤新药
——攻克癌症的希望[J]. 癌变·畸变·突变, doi: 10.3969/j.issn.1004-616x.2014.04.015.

参考文献

[1] Cohnheim J. Congenitales，quergestreiftes Muskelsarkon der Nireren[J]. Virchows Arch，1875，65：64-69.

[2] 窦骏. 肿瘤干细胞[M]. 南京：东南大学出版社，2009.

[3] Rolf Bjerkvig，Berit BT，Karen S，et al. The origin of the cancer stem cell：current controversies and new insights[J]. J Nature Reviews Cancer，2005，5(11)：899-904.

[4] Blair A，Hogge DE，Ailles LE，et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo[J]. Blood，1997， 89(9)：3104-3112.

[5] Lapidot T，Sirard C，Vormoor J，et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice[J]. Nature，1994，367(6464)：645-648.

[6] Bonnet D，Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med，1997，3(7)：730-737.

[7] Al-Hajj M，Wicha MS，Benito-Hernandez A，et al. Prospec-tive identification of tumorigenic breast cancer cells[J]. Proc Natl Acad Sci USA，2003，100(7)：3983-3988.

[8] Ponti D，Costa A，Zaffaroni N，et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties[J]. Cancer Res，2005，65 (13)：5506-5511.

[9] Singh SK，Clarke ID，Hide T，et al. Cancer stem cells innervous system tumors[J]. Oncogene，2004，23(43)：7267-7273.

[10] Singh SK，Clarke ID，Terasaki M，et al. Identification of a cancer stem cell in human brain tumors[J]. Cancer Res，2003， 63 (18)：5821-5828.

[11] Singh SK，Hawkins C，Clarke ID，et al. Identification of human brain tumour initiating cells[J]. Nature，2004， 432 (7015)：396-401.

[12] Hemmati HD，Nakano I，Lazareff JA，et al. Cancerous stem cells can arise from pediatric brain tumors[J]. Proc Natl Acad Sci USA，2003，100(25)：15178-15183.

[13] Richardson GD，Robson CN，Lang SH，et al. CD133，a novel marker for human prostatic epithelial stem cells[J]. J Cell Sci，2004，117(Sup 16)：3539-3545.

[14] Collins AT，Berry PA，Hyde C，et al. Prospective identifi-cation of tumorigenic prostate cancer stem cells[J]. Cancer Res，2005，65(23)：10946-10951.

[15] Li C，Heidt DG，Mollenberg N，et al. Identification of pancreatic cancer stem cells[J]. Pancreas，2005，31(4)：452.

[16] Fiegel HC，Gluer S，Roth B，et al. Stem-like cells in human hepatoblastoma[J]. J Histochem Cytochem，2004，52(11)： 1495-1500.

[17] Kim CF，Jackson EL，Woolfenden AE，et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer[J]. Cell，2005，121(6)：823-835.

[18] O’Brien CA，Pollett A，Gallinger S，et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice[J]. Nature，2007，445(7123)：106-110.

[19] Ricci-Vitiani L，Lombardi DG，Pilozzi E，et al. Identification and expansion of human colon-cancer-initiating cells[J]. Nature，2007，445(7123)：111-115.

[20] Dalerba P，Dylla SJ，Park IK，et al. Phenotypic characterization of human colorectal cancer stem cells[J]. Proc Natl Acad Sci USA，2007，104(24)：10158-10163.

[21] Monzani E，Facchetti F，Galmozzi E，et al. Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential[J]. Eur J Cancer，2007，43(5)：935-946.

[22] Frank NY，Margaryan A，Huang Y，et al. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma[J]. Cancer Res，2005，65(10)：4320-4333.

[23] Long VN，Robert V，Peter D，et al. Cancer stem cells：an evolving concept[J]. Nature Reviews Cancer ，2012，12：133-143.

[24] Arnout GS，Hugo JS，Daniel ES，et al. Lineage tracing reveals lgr5+ stem cell activity in mouse intestinal adenomas[J]. Science，337(6095)：730-735.

[25] Whyte WA，Bilodeau S，Orlando DA，et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation[J]. Nature，2012，482(7384)：221-225.

[26] Sachlos E，Risue?o RM，Laronde S，et al. Identi?cation of drugs including a dopamine receptor antagonist that selectively target cancer stem cells[J]. Cell，149(6)：1284-1297.

[27] Al-Hajj M，Clarke MF. Self-renewal and solid tumor stem cells[J]. Oncogene，2004，23(43)：7274-7282.

[28] Chambers I，Smith A. Self-renewal of teratocarcinoma and embryonic stem cells[J]. Oncogene，2004，23(43)：7150-7160.

[29] Li LH，Neaves WB. Normal stem cells and cancer stem cells：the niche matters[J]. Cancer Res，2006，66(9)：4553-4557.

[30] Kucia M，Reca R，Miekus K，et al. Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms：pivotal role of the SDF-1-CXCR4 axis[J]. Stem Cells，2005，23(7)：879-894.

[31] Staud F，Pavek P. Breast cancer resistance protein (BCRP/ ABCG2) [J]. Int J Biochem Cell Biol，2005，37(4)： 720-725.

[32] Leslie EM，Deeley RG，Cole SP. Multidrug resistance proteins：role of P-glycoprotein，MRP1，MRP2 and BCRP (ABCG2) in tissue defense[J]. Toxicol Appl Pharmacol， 2005，204(3)：216-237.

[33] Rosen JM，Jordan CT. The increasing complexity of the cancer stem cell paradigm[J]. Science，2009，324(5935)：1670-1673.

[34] Houghton J，Stoicov C，Nomura S，et al. Gastric cancer originating from bone marrow-derived cells[J]. Science，2004， 306(5701)：1568-1571.

[35] Bao S，Wu Q，Li Z，et al. Targeting cancer stem cells through L1CAM suppresses glioma growth[J]. Cancer Res，2008， 68(15)：6043-604.

[36] Kim CF，Jackson EL，Woolfenden AE，et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer[J]. Cell，2005，121(6)：823-835.

[37] Polyak K，Hahn WC. Roots and stems：stem cells in cancer[J]. Nat Med，2006，12(3)：296-300.

[38] Kai T，Spradling A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries[J]. Nature，2004，428(6982)：564-569.

[39] Huntly BJ，Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research[J]. Nat Rev Cancer， 2005，5(4)：311-321.

[40] Yamashita YM，Fuller MT，Jones DL. Signaling in stem cell niches：lessons from the Drosophila germline[J]. J Cell Sci，2005，118(Sup 4)：665-672.

[41] Moore KA，Lemischka IR. Stem cells and their niches[J]. Science，2006，311(5769)：1880-1885.

[42] Niemann C. Controlling the stem cell niche：right time， right place，right strength[J]. Bioessays，2006，28(1)：1-5.

[43] Dontu G，Jackson KW，McNicholas E，et al. Role of Notch signaling in cell-fate determination of human mammary stem/rogenitor cells[J]. Breast Cancer Res，2004，6 (6)：605-615.

[44] Varjosalo M，Li SP，Taipale J. Divergence of hedgehog signal transduction mechanism between Drosophila and mammals[J]. Dev Cell，2006，10(2)：177-186.

[45] Taipale J，Beachy PA. The Hedgehog and Wnt signaling pathways in cancer[J]. Nature，2001，411(6835)：349-354.

[46] Beachy PA，Karhadkar SS，Berman DM. Tissue repair and stem cell renewal in carcinogenesis[J]. Nature，2004， 432(7015)：324-331.

[47] Dvorak P，Dvorakova D，Hampl A. Fibroblast growth factor signaling in embryonic and cancer stem cells[J]. FEBS Lett，2006，580(12)：2869-2874.

[48] Antonio P，Kimberly F，Paola R，et al. Targeting Notch to target cancer stem cells[J]. Clin Cancer Res，2010，16(12)： 3141-3152.

[49] Tannishtha R，Sean JM，Michael FC，et al. Stem cells， cancer，and cancer stem cells[J]. Nature，2001，414： 105-111.

[50] Takebe N，Harris PJ，Ronald QW，et al. Targeting cancer stem cells by inhibiting Wnt，Notch and Hedgehog pathways[J]. Nat Rev Clin Oncol，2010，8(2)：97-106.

[51] Andrzej D，Sid A，Peter K. Vismodegib[J]. Nat Rev Drug Discov，2012，11：437-438.