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7 s8 U% U$ ^* E5 X6 n2001年nature刊登了一篇综述，系统介绍了肿瘤干细胞的定义及其特性。原文见：6 R& Y1 _: z" l* d
% w, w) u2 R' Y) f2 Xhttp://mcardle.oncology.wisc.edu/alexander/PDF/Reya.pdf
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8 M4 ]9 \' E% A; ^: j9 _该文通过对造血干细胞及造血系统肿瘤干细胞特性的介绍，使我们对肿瘤干细胞有了初步的认识，其中，很多经典的图片。! B Q9 v9 d3 J2 w
( m' V7 D% ^1 F
有些研究表明，阻止细胞死亡在髓性白血病发生中其重要作用， 且基因转化可局限于祖细胞：
7 d8 a. a3 K+ n& f35. Lagasse, E. & Weissman, I. L. bcl-2 inhibits apoptosis of neutrophils but not their engulfment by
! C6 L( i8 ^8 t: V X6 g% Smacrophages. J. Exp. Med. 179, 1047–1052 (1994).
6 v& ~7 g/ t1 w3 I+ G36.Traver, D., Akashi, K., Weissman, I. L. & Lagasse, E. Mice defective in two apoptosis pathways in the/ ?1 m! V; a+ M% d1 h3 @# [8 i
myeloid lineage develop acute myeloblastic leukemia. Immunity 9, 47–57 (1998).
8 U( [) _6 h8 x& ^# R" E" v
, ^) Q: ~4 C$ H0 r( C/ Q
+ `. ^( m1 p) \β-catenin和Wnt路径的失调在癌症中很普遍，该途径的靶向过 表达可以导致转基因鼠发生肿瘤：' B& F% U6 G# P. R
37.Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).
. e$ A; |# W" x, o. i" s6 Y" c38.Tsukamoto, A., Grosschedl, R., Guzman, R., Parslow, T. & Varmus, H. E. Expression of the int-1 gene0 j6 f+ n, R/ H: {* i! H0 _
in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and* [0 W6 J) h. K0 J! b. n+ v
female mice. Cell 55, 619–625 (1988).
3 _. G/ t; W4 n8 F0 p, Q+ i
, C) ]1 P% ^3 }) ? A1 ^# q
0 w9 i, f, t- o如果将肿瘤视为一个异常的器官，那么普通干细胞的原则也可以 用于理解肿瘤的发生：+ P- J+ O0 k z# z2 e9 `, V& p
12.Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities.
. Z+ u' d9 s* _) HScience 287, 1442–1446 (2000).
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287–298 (1997).
4 G. T7 W* B3 \' {* I3 a( c45.Kummermehr, J. & Trott, K.-R. in Stem Cells (ed. Potten, C. S.) 363–399 (Academic, New York, 1997).
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小鼠骨髓瘤细胞在体外克隆形成中仅1/10000到1/100中可以形成 克隆。白血病细胞移植到小鼠体内，也仅1-4%可以形成克隆：: i4 y) X& s# q( H
53.Park, C. H., Bergsagel, D. E. & McCulloch, E. A. Mouse myeloma tumor stem cells: a primary cell1 N. t; T5 ^! |7 k& E: a3 n1 e( C
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Rep. 51, 415–421 (1967).
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有研究者鉴别出AML中CD34+CD38-细胞具有比其他类型细胞更强 的克隆形成能力：8 N/ s1 P, U; C+ i/ U4 `* f
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3 G0 X4 q0 F( w- g& l实体癌中也发现细胞具有表型的不均一性，且仅少部分细胞在体 外培养或体内种植时具有克隆形成能力：
# I8 h. C( T) S3 n; n46. Fidler, I. J. & Kripke, M. L. Metastasis results from preexisting variant cells within a malignant tumor.
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47. Fidler, I. J. & Hart, I. R. Biological diversity in metastatic neoplasms: origins and implications. Science
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58. Southam, C. M. & Brunschwig, A. Quantitative studies of autotransplantation of human cancer.
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4 H7 l- \! b G$ A0 O2 ?1 c
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研究表明，在远离原发肿瘤的部位可以检测到播散的肿瘤细胞， 但并不一定形成远处转移：
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Cancer 14, 971–978 (1961).
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$ v9 f; u! o1 m7 H% n
% I: U o6 O5 ]6 B# V对该现象有两种可能的解释：1，免疫监督在形成可检测的肿瘤 前有效的杀死播散肿瘤细胞；2，大多数肿瘤细胞缺乏形成新肿 瘤的能力，该能力只有少数肿瘤干细胞具有：
% d6 L, ~4 k o8 s2 L8 M+ W45.Kummermehr, J. & Trott, K.-R. in Stem Cells (ed. Potten, C. S.) 363–399 (Academic, New York, 1997).* j/ {( Z" `# u" j
& n+ {2 ^! h% ^
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正由于肿瘤干细胞的存在，使得当前的治疗无法根除实体瘤，虽 然可以缩小转移瘤体积，但不久就会复发：4 k: ~2 s% Q4 y3 e8 k8 Z9 Z
61.Williams, S. D. Treatment of disseminated germ cell tumors with cisplatin, bleomycin, and either
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有两种解释：1，治疗失败时由于肿瘤细胞在药物刺激过程中产 生耐药；2，是由于当前的治疗无法杀死肿瘤干细胞。2 ?; I" C8 ]) K) v" i8 Q
1 [+ `7 `' S4 k+ D( W+ D
0 K( P5 U0 {2 B) n( }0 ]$ Y从不同组织来源的普通干细胞比其组织来源的普通细胞更能耐受 化疗：
" ]* k/ K1 l7 p3 W$ ?64.Harrison, D. E. & Lerner, C. P. Most primitive hematopoietic stem cells are stimulated to cycle rapidly
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" ]0 q& m5 h( q或者由于多药耐药基因等ABC转运体的过表达：
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造血干细胞可以分化成其他非造血性组织或器官，如脑，肝等：
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& ^ O* R# A2 t, ]- G ~原始造血多能干细胞可以分化成三类细胞：长期自我更新造血干 细胞，短期自我更新造血干细胞和不具有自我更新能力的多功能 祖细胞：) G. Z- ~2 i, g
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/ }( K- }* \( L& b3 J" {造血干细胞的表型和功能特性见以下综述:
* s; s8 _+ i# p, [# r( ?, D12.Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities.
O* E. K# {$ E$ j: G' a* oScience 287, 1442–1446 (2000).8 c$ n. I# \+ B7 j4 x P$ Q
$ ?* `% i, b& s4 a6 h
$ q* }7 `$ B: M4 V# @鉴定出保持造血干细胞活性的培养条件：
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) v. [$ i) k0 S1 g c有证据显示，与癌症相关的一些通路也与调节正常干细胞发育的通路相关。见图2：
0 R1 F) b. z# j; jWNT通路相关肿瘤为结肠癌和上皮肿瘤：; o% `0 ?: k m2 T% C& e- I
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SHH途径相关肿瘤为成神经管细胞瘤和基底细胞癌：( V8 X$ Y' O3 H$ |& i- b
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NOTCH途径相关肿瘤为T细胞性白血病：
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+ ], G1 z8 o. l& y4 t4 Mby constitutive Notch1 signaling. Nature Med. 6, 1278– 1281 (2000).8 P6 ]! h/ u5 J9 I
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' C* ~& c5 v* _0 i% z
4 e" V3 [! \( A# p/ [+ s基因芯片技术可用于分析恶性肿瘤细胞的基因表达情况，从而将 肿瘤细胞分成不同亚组，他们具有不同的突变表型：
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) r [4 L' T' h ?2 v7 @8 R3 A( ]. z8 f0 K7 y
显微解剖形态学相似的肿瘤细胞群体有助于获得同质细胞群体的 特性：
, s. q; _. z5 L75.Sgroi, D. C. et al. In vivo gene expression profile analysis of human breast cancer progression. Cancer8 {, N' d* b8 B8 F* [# k& J
Res. 59, 5656–5661 (1999)./ V, Q9 d5 l; q: \5 u
76.Leethanakul, C. et al. Distinct pattern of expression of differentiation and growth-related genes in8 |, b+ j5 U: b0 I1 \* u
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8 ?$ K9 U9 ]$ B. n$ I @$ x
总结：
2 \4 e# b# Z, g/ V( p1 [1，自我更新是正常组织或肿瘤中干细胞的标志性特点；
6 a- |( \7 i5 B7 v+ x# R2 r; }2，在造血系统，长期自我更新细胞局限于少数长期HSC和一些淋 巴细胞，其他细胞类型无自我更新潜能；
4 O9 X8 d6 o/ z' O0 q3，长期存在的细胞更可能累计突变从而导致肿瘤形成。因此， 导致髓性白血病的基因改变必定发生在长期HSC或其获得自我更 新能力的后代上。白血病患者中，长期HSC细胞中常有白血病相 关异位现象，该现象强烈支持白血病突变常常在HSC中累积，导 致某些淋巴瘤的突变可能在淋巴细胞中累积，从而使其具有长期 自我更新能力；
" y3 j+ _7 \; A% |4，其他正常组织也具有自我更新能力的干细胞，如上皮，实体 肿瘤发展过程中基因改变的逐步累积也发生在干细胞或其具有自 我更新能力的后代上；* `2 `* ?( J9 u$ E8 }5 A' ^. e
5，不同组织中，有不同信号途径控制干细胞的自我更新。但在 个别组织中，普通干细胞和肿瘤细胞通过同一信号途径控制细胞 增值，例如，WNT途径调节血液和上皮中干细胞的自我更新，但 在有些上皮细胞癌中，也同样有WNT信号通路的激活；% P' D9 [3 ]) b' |/ z
6，理解了信号途径在普通干细胞和肿瘤细胞中的作用，有助于 利用普通干细胞再生药物和鉴别出肿瘤干细胞的靶点从而为开发 抗肿瘤药物服务；& ]0 d0 l) K. j6 a: x
7，大部分肿瘤组织中有肿瘤干细胞的存在，它们可以无限制的 自我更新，而大部分干细胞仅具有有限的增值潜能；
, P. D; s/ r5 v8，为了治愈癌症，必须杀死肿瘤干细胞。为此，必须鉴别出该 类细胞的特性。) ]6 F6 T2 `7 y4 @8 C
5 F, y% a9 Q0 ?* s& f2 A+ ~+ ^, |例如，为了阻止凋亡发生，增强癌基因bcl-2的表达，结果导致 体内的造血干细胞数目增加，提示，细胞死亡在调节造血干细胞 稳态中起作用：
0 D% t( F7 E# {0 m& i. d14. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic overexpression of BCL-2 in the hematopoietic system6 u. R# U. r; O, \. d8 V+ L
protects transgenic mice from the consequences of lethal irradiation. Blood 91, 2272–2282 (1998).
& K) u6 J- A. y% m0 v8 d6 N6 g! L, E15.Domen, J. & Weissman, I. L. Hematopoietic stem cells need two signals to prevent apoptosis; BCL |
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发表于 2009-10-23 21:40
发表于 2009-12-17 10:32
