Melanoma stem cell markers and targeted therapies: awareness and pertinence

doi:10.3969/j.issn.2095-4344.0406

Abstract

Abstract:

BACKGROUND: Melanomas, a highly malignant tumor of the skin, have no effective therapy to date.
OBJECTIVE: To review the melanoma stem cell markers identified and existing therapies.
METHODS: We retrieved database of CNKI and PubMed for articles addressing melanoma stem cell markers and targeted therapies, which were published from January 2010 to December 2016. The key words were “melanoma, cancer stem cell, marker, therapy” in Chinese and English, respectively.
RESULTS AND CONCLUSION: Forty articles were included in the final review. It is important to separate cancer stem cells from tumor cells by tumor stem cell markers for the study of tumor growth, recurrence, metastasis and drug resistance. There are still no generally recognized markers of melanoma stem cells, but the generally studied markers are CD20, CD133, CD271, ABCB5 and SOX10. To date, we have a poor understanding of melanoma stem cell markers, and further investigations on the markers and targeted therapies are warranted.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Melanoma, Neoplastic Stem Cells, Biological Markers, Tissue Engineering

CLC Number:

R394.2

Wu Xing, Yuan Ding-fen. Melanoma stem cell markers and targeted therapies: awareness and pertinence[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(1): 152-157.

Figures/Tables 2

2.1 肿瘤干细胞早在1867年就有人提出了肿瘤干细胞的概念，但是由于当时科学技术水平有限，未能分离出肿瘤干细胞。1977年在骨髓瘤细胞的体外软琼脂培养基克隆形成实验中，Hamhurger等[4]发现只有不到0.2%的细胞能形成克隆，不到4%的细胞能在NOD/SCID小鼠脾内形成肿瘤，有人提出将这小部分具有成瘤能力的细胞称为肿瘤干细胞。1997年，Bonnet等[5]首次从急性髓性白血病中分离出CD34+/CD38-表型细胞，且将其移植至NOD/SCID小鼠可以引起急性髓性白血病的发生，而其他细胞均不能引起急性髓性白血病的发生，从而证实了肿瘤干细胞的存在。2001年，Reya等[6]正式提出了肿瘤干细胞的概念。在肿瘤组织中存在着一小部分具有干细胞特性的肿瘤细胞亚群，它们具有自我更新能力以及多向分化潜能，在肿瘤的形成和生长过程中起着重要作用，称之为肿瘤干细胞[7]。 2.2 肿瘤干细胞的起源肿瘤干细胞起源目前尚未完全清楚，大致有以下3种学说：①肿瘤干细胞来源于成体干细胞。致癌性的突变使得正常成体干细胞内自我更新及分化增殖的调控机制过度激活从而转变为肿瘤干细胞。Lenkiewicz等[8]证实脑肿瘤的肿瘤干细胞标志物CD133、nestin等与神经干细胞标志物相同。此外，部分乳腺癌的肿瘤干细胞表型也与其干细胞表型一致；②肿瘤干细胞来源于已分化的细胞(祖细胞甚至是终末分化细胞)。在外界因素的作用下，已分化的细胞可以去分化获得干细胞的特性，成为肿瘤干细胞。如转染MOZ-TIF2癌基因给祖细胞能够诱导产生急性髓性白血病；③肿瘤干细胞来源于细胞融合。Moore等[9]发现在慢性幽门螺杆菌感染的C57BL/6小鼠中，造血干细胞选择性地迁移至胃上皮，诱导胃癌的发生，说明肿瘤干细胞可能由正常的干细胞和突变的分化细胞融合产生。 2.3 肿瘤干细胞的分离当前最常用的筛选和分离肿瘤干细胞的方法是通过其细胞表面标记物利用流式细胞分选术或磁性活化细胞分选术进行[10]。①流式细胞分选术，又称荧光活化细胞分选术，是利用ABCG2能够高效地将DNA荧光染料Hoechst33343泵出细胞外的特性，经流式细胞仪分选出Hoechst33343拒染的ABCG2高表达的侧群细胞。侧群细胞存在于大多数肿瘤细胞系中，拥有较强的生长繁殖能力并且具有多向分化潜能，因此不少研究者将侧群细胞作为部分肿瘤的肿瘤干细胞进行相关研究，如急性髓性白血病、脑肿瘤、前列腺癌、乳腺癌、肝癌、视网膜母细胞瘤等；②磁性活化细胞分选术，又称为免疫磁珠分选术，是利用磁珠免疫标记的特异性单克隆抗体与肿瘤干细胞表面特异性的抗原相结合，再在外部磁场的作用下，与特异性单克隆抗体结合的肿瘤干细胞经免疫磁珠吸附在磁式分选柱上，而未与特异性单克隆抗体结合的肿瘤干细胞则无法停留在磁场中，最后通过洗柱、收集，从而得到肿瘤干细胞。肺腺癌以及胶质瘤的肿瘤干细胞就是利用这种方法获得的。 2.4 黑色素瘤干细胞随着对肿瘤干细胞相关研究的不断深入，人们在多种肿瘤组织和肿瘤细胞系中发现了肿瘤干细胞的存在，如乳腺癌、脑肿瘤、结肠癌等。Fang等在黑色素瘤中首次发现一种在胚胎干细胞培养基中表达CD20的无黏附力的球形细胞，其在一定的培养条件下可分化成黑素细胞、骨软骨形成细胞、脂肪形成细胞等多种细胞系，且在体外连续传代培养超过8个月后仍保持分化能力，说明其具有自我更新及多向分化潜能，被认为是黑色素瘤干细胞[11]。SCID/NOD小鼠实验也证实黑色素瘤干细胞具有较强的成瘤能力。与定位于毛囊隆突部位的黑素干细胞对比研究更进一步揭示了黑色素瘤干细胞的生物学特性，如黑素干细胞的标志物CD133在黑色素瘤干细胞中表达增加，提示它们之间存在一定的联系。文辉才等[12]利用无血清培养基培养人恶性黑色素瘤A375细胞系，获得黑色素瘤球体细胞(图1)，其具有干细胞特性，迁移能力和致瘤能力强，高表达免疫标记CD20、CD133，说明恶性黑色素瘤存在肿瘤干细胞。"

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