贡献一片老文：干细胞、肿瘤和肿瘤干细胞（Stem cells,cancer, and cancer stem cells)--经典文献阅读

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2001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：( P2 {$ j  s9 O8 `

/ Z' f$ |, S7 z. k1 Lhttp://mcardle.oncology.wisc.edu/alexander/PDF/Reya.pdf- u( {9 d9 y* B( K! s( f6 S& I

: [+ @+ c6 ?- g9 U8 i6 V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。
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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：" E6 ~  ^+ N4 Y
35. Lagasse, E. & Weissman, I. L. bcl-2 inhibits      apoptosis of neutrophils but not their engulfment by
) G9 ?9 k3 N1 `4 E4 v0 Xmacrophages. J. Exp. Med. 179, 1047–1052 (1994).
7 Q- H" {- \  [) |# h/ f9 }/ [36.Traver, D., Akashi, K., Weissman, I. L. & Lagasse, E.      Mice defective in two apoptosis pathways in the
; J: I' }( X2 l  u, O1 D, |7 Emyeloid lineage develop acute myeloblastic leukemia.      Immunity 9, 47–57 (1998)./ k) X/ c: s; q( }+ M- h9 q% K! i/ L

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1 f% J* a" _4 \: Rβ-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：
7 [1 V8 }* a- |. q1 _37.Polakis, P. Wnt signaling and cancer. Genes Dev. 14,      1837–1851 (2000).8 d& N+ ^, G! A' }$ e
38.Tsukamoto, A., Grosschedl, R., Guzman, R., Parslow,      T. & Varmus, H. E. Expression of the int-1 gene
4 _8 U. x4 w+ P. N; I5 kin transgenic mice is associated with mammary gland      hyperplasia and adenocarcinomas in male and
' q  u1 T1 T1 r* B4 hfemale mice. Cell 55, 619–625 (1988).- ~% u. e1 M) H7 j9 D, k. T

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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：
4 Z2 a0 F9 }, O! l12.Weissman, I. L. Translating stem and progenitor cell      biology to the clinic: barriers and opportunities.
5 V, b  c" x) H, x  ]9 E8 }) }Science 287, 1442–1446 (2000).1 s4 H, K: J. c9 P6 X0 \5 X7 N6 z* B
44.Morrison, S. J., Shah, N. M. & Anderson, D. J.      Regulatory mechanisms in stem cell biology. Cell 88,
0 b, A+ H* _- y9 b2 V6 Q287–298 (1997).5 D% |" b/ R  v4 I. Q
45.Kummermehr, J. & Trott, K.-R. in Stem Cells (ed.      Potten, C. S.) 363–399 (Academic, New York, 1997).
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- ~: {, {: e7 }* K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：
3 y$ G+ b5 X' i9 d  k3 i4 ?53.Park, C. H., Bergsagel, D. E. & McCulloch, E. A.      Mouse myeloma tumor stem cells: a primary cell
" \7 L) |+ w) t) Aculture assay. J. Natl Cancer Inst. 46, 411–422 (1971).
0 g, Y' _3 H* ^6 U54.Bruce, W. R. & Gaag, H. v. d. A quantitative assay      for the number of murine lymphoma cells capable( Q% a( [; B+ V; n  ]0 u- M& C
of proliferation in vivo. Nature 199, 79–80 (1963).2 @7 w/ o/ b. J) {
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56.Bergsagel, D. E. & Valeriote, F. A. Growth      characteristics of a mouse plasma cell tumor. Cancer      Res. 28,
0 j4 c4 r5 a/ C& h2187–2196 (1968).$ k( @& P1 Q9 i; J* `5 p5 S

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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：
5 q( V' Y& ~9 g57.Bonnet, D. & Dick, J. E. Human acute myeloid leukemia      is organized as a hierarchy that originates$ W: H6 l* ?1 J) s! [& ?0 w7 m
from a primitive hematopoietic cell. Nature Med. 3, 730 –737 (1997).
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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：6 t7 v9 B3 G# w# M# T
46. Fidler, I. J. & Kripke, M. L. Metastasis results      from preexisting variant cells within a malignant tumor.
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217, 998–1003 (1982).
7 g0 T6 e/ I! r1 ~48.Heppner, G. H. Tumor heterogeneity. Cancer Res. 44,      2259–2265 (1984).7 w7 K! r7 x* @
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Cancer 14, 971–978 (1961).
1 l, i4 U- }  x8 u; R* X. f: i! n59.Hamburger, A. W. & Salmon, S. E. Primary bioassay of      human tumor stem cells. Science 197,# ?% u; n5 @" }5 e- R) v1 s
461–463 (1977).
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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：' D- i2 y; E$ J
58. Southam, C. M. & Brunschwig, A. Quantitative studies      of autotransplantation of human cancer.' d( n. K; H! `; q4 A: f4 f% b
Cancer 14, 971–978 (1961).. ^) \1 g& ^) i( O  d* r
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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：: s! n3 X6 d+ w( u6 v
45.Kummermehr, J. & Trott, K.-R. in Stem Cells (ed.      Potten, C. S.) 363–399 (Academic, New York, 1997).
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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：
( R+ V. `: X, Q7 k/ ^/ m0 e5 M61.Williams, S. D. Treatment of disseminated germ cell      tumors with cisplatin, bleomycin, and either
% I. u4 Z/ k; Q# zvinblastine or etoposide. N. Engl. J. Med. 316, 1435– 1439 (1987).
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endocrine therapy in metastatic breast cancer. Cancer      Treatment Rev. 26, 151–168 (2000).
9 N0 m) G: Q5 p  k- `63. Lippman, M. E. High-dose chemotherapy plus      autologous bone marrow transplantation for
% c0 y) \/ M4 }0 R3 b( V7 m/ ?metastatic breast cancer. N. Engl. J. Med. 342, 1119– 1120 (2000).
+ p" Y6 T- ~& t5 g( [0 z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。' [! z- H8 c8 k  Z% \7 T8 [

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! D+ b& ?. r( X% ]6 v8 Z6 a+ v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：
  E8 w1 y5 [" Y3 n1 K/ n/ t64.Harrison, D. E. & Lerner, C. P. Most primitive      hematopoietic stem cells are stimulated to cycle rapidly
- `/ f3 Z/ K5 d  {  k9 Oafter treatment with 5-fluorouracil. Blood 78, 1237– 1240 (1991).
. v$ s, I4 x3 v) S$ S这可能时由于该类细胞的抗凋亡蛋白表达水平较高，
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66.Peters, R., Leyvraz, S. & Perey, L. Apoptotic      regulation in primitive hematopoietic precursors. Blood# c1 R" h# b# [7 `; T- u
92, 2041–2052 (1998).
. P! ?  h3 y& ]67. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic      overexpression of BCL-2 in the hematopoietic system, A$ u' U) e+ \9 U4 r" Z
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或者由于多药耐药基因等ABC转运体的过表达：6 ?- b- J8 E) V& k+ o
69. Zhou, S. et al. The ABC transporter Bcrp1/ABCG2 is      expressed in
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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：
$ \  @! W4 p( j% d6. Petersen, B. E. et al. Bone marrow as a potential      source of hepatic oval cells. Science 284, 1168–1170      (1999).' |- p8 X" t. y- _9 U
7. Brazelton, T. R., Rossi, F. M. V., Keshet, G. I. &      Blau, H. M. From marrow to brain: expression of
0 `/ e, f( T- h; aneuronal phenotypes in adult mice. Science 290, 1775– 1779 (2000).! r6 e" Y; i3 O: B
8. Mezey, E., Chandross, K. J., Harta, G., Maki, R. A. &      McKercher, S. R. Turning blood into brain: cells- S& @! _% h: X* ]- F, u# j9 t
bearing neuronal antigens generated in vivo from bone      marrow. Science 290, 1779–1782 (2000).
, t1 F, w# r0 G% @9. Lagasse, E. et al. Purified hematopoietic stem cells      can differentiate to hepatocytes in vivo. Nature3 a7 I/ ?7 r: y5 T" ~, G8 [% A
Med. 6, 1229–1234 (2000).8 G' W9 e& B7 a, D
10.Krause, D. S. et al.Multi-organ, multi-lineage      engraftment by a single bone marrow derived stem cell." a1 A& s1 Q) c5 z6 _8 w3 F
Cell 105, 369–377 (2001).) Y& z- D' d1 `& P
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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：
$ @; R3 s+ L, q0 J: @  B2. Morrison, S. J. & Weissman, I. L. The long-term      repopulating subset of hematopoietic stem cells is8 W1 u. w; n5 y" I& f: ~. d
deterministic and isolatable by phenotype. Immunity 1,      661–673 (1994).  B) }% m4 d% ]3 I, {) J  u

) ?7 |4 i' X5 `, R2 e, K8 I, G11.Morrison, S. J., Wandycz, A. M., Hemmati, H. D.,      Wright, D. E. & Weissman, I. L. Identification of a
/ `6 R; \0 }, Klineage of multipotent hematopoietic progenitors.      Development 124, 1929–1939 (1997).
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造血干细胞的表型和功能特性见以下综述:9 S. y( r/ \/ F6 p
12.Weissman, I. L. Translating stem and progenitor cell      biology to the clinic: barriers and opportunities.; C# F/ F/ [, m
Science 287, 1442–1446 (2000).
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鉴定出保持造血干细胞活性的培养条件：$ }. W4 c" g  U3 v' L# e0 J, b5 s
13.Miller, C. L. & Eaves, C. J. Expansion in vitro of      adult murine hematopoietic stem cells with      transplantable
, k0 O. l, [- K- @1 K7 rlympho-myeloid reconstituting ability. Proc. Natl Acad.      Sci. USA 94, 13648–13653 (1997)! e" S. W9 V# \7 O' i4 A1 b
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( `/ X% s1 v' j. Z8 R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：- D  x- x; M+ ]* Z- I
WNT通路相关肿瘤为结肠癌和上皮肿瘤：# N5 ?! g; W. B2 I& p
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* j. _) w( @" {* y* f6 x* G" `4 uSHH途径相关肿瘤为成神经管细胞瘤和基底细胞癌：# U% w# D, n/ N7 L' D
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NOTCH途径相关肿瘤为T细胞性白血病：7 l+ x5 n" @  ?1 M3 r$ p3 b2 y
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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：5 B8 T6 h% ~+ v" S
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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：  b5 k" X7 e+ i9 w
75.Sgroi, D. C. et al. In vivo gene expression profile      analysis of human breast cancer progression. Cancer
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总结：# r; K% y! |! V" m8 o. q% h% Q
1，自我更新是正常组织或肿瘤中干细胞的标志性特点；
( k* {6 U; Q) R1 q0 {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；
0 o$ H; b! v! |3，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；
5 o' i9 T# R( K! W! C4，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；
; W% n! c8 \, X. h" I4 ]0 r5，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；' S" P% N  l9 C% T
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；5 i8 ~) k# p* L* M2 I# C; ^
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；: a) l/ D9 J8 L( u! n$ `# A: C% C
8，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。
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5 P9 y9 E* S' C" S" b5 A# f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：
" E; @8 ^/ p4 M0 @! [5 y, U14. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic      overexpression of BCL-2 in the hematopoietic system
. U! @' F* p% @. _protects transgenic mice from the consequences of lethal      irradiation. Blood 91, 2272–2282 (1998)." W2 ~+ \3 I7 v0 y9 ^
15.Domen, J. & Weissman, I. L. Hematopoietic stem cells      need two signals to prevent apoptosis; BCL