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$ s$ D7 `/ @1 m2 }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：
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http://mcardle.oncology.wisc.edu/alexander/PDF/Reya.pdf
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; c7 W( m* ~% p, v! W/ Y6 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。2 T" k8 N* l! [4 ~) s8 W% \( P: U
# l9 I3 b' b% W5 x+ j- ^
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：
+ t5 D. b9 v- z1 X35. Lagasse, E. & Weissman, I. L. bcl-2 inhibits apoptosis of neutrophils but not their engulfment by
8 `- J! R4 U, G1 ?macrophages. J. Exp. Med. 179, 1047–1052 (1994).
4 B& x+ I" n. {) h% G8 S3 A36.Traver, D., Akashi, K., Weissman, I. L. & Lagasse, E. Mice defective in two apoptosis pathways in the
+ A0 a7 {: b' c" A3 x! G9 Zmyeloid lineage develop acute myeloblastic leukemia. Immunity 9, 47–57 (1998). F9 j7 B. F, u
9 N& {5 ]5 ]$ m- L
! {8 c& f$ Q1 {+ }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：
/ ~& n) P7 }$ Z4 c @# z37.Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).
/ E# ?! O7 `' j- y) G38.Tsukamoto, A., Grosschedl, R., Guzman, R., Parslow, T. & Varmus, H. E. Expression of the int-1 gene7 S0 y: A8 r4 Z/ b1 o
in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and
0 k( \% G" n! P; ~4 z- x% |female mice. Cell 55, 619–625 (1988). d3 ^; S5 ~/ i7 b: \0 {
3 t6 B! K; s+ H
0 ^; S7 I) `1 C! W8 C! \! w4 K8 t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：7 N( p! `: e. C9 e) f$ n
12.Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities.
' i; Z4 `" w5 ~; G% ^9 h# JScience 287, 1442–1446 (2000).7 q9 _( T* ]" t. C1 `
44.Morrison, S. J., Shah, N. M. & Anderson, D. J. Regulatory mechanisms in stem cell biology. Cell 88," ?$ l6 t, r: M# M9 {
287–298 (1997).! J0 L1 l6 Z% a& z- L
45.Kummermehr, J. & Trott, K.-R. in Stem Cells (ed. Potten, C. S.) 363–399 (Academic, New York, 1997).
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) a6 D' q8 C# s7 B0 q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：
$ j+ w& Y4 ^6 f" c+ `1 J53.Park, C. H., Bergsagel, D. E. & McCulloch, E. A. Mouse myeloma tumor stem cells: a primary cell. U; F2 j/ p: |; O
culture assay. J. Natl Cancer Inst. 46, 411–422 (1971).* v( U! U& ^1 }2 L: Y
54.Bruce, W. R. & Gaag, H. v. d. A quantitative assay for the number of murine lymphoma cells capable; q! U4 d1 K9 ?4 {
of proliferation in vivo. Nature 199, 79–80 (1963).
! @: A1 _3 y; a. b9 i3 e: W5 o( P0 m55.Wodinsky, I., Swiniarski, J. & Kensler, C. J. Spleen colony studies of leukemia L1210. I. Growth
" E- T7 ?" l, Kkinetics of lymphocytic L1210 cells in vivo as determined by spleen colony assay. Cancer Chemother.
. ~3 z; z d) JRep. 51, 415–421 (1967)." r" u3 V& o; w
56.Bergsagel, D. E. & Valeriote, F. A. Growth characteristics of a mouse plasma cell tumor. Cancer Res. 28,3 R4 [8 ~ ^) F& _
2187–2196 (1968).% s0 J8 C9 P* n* @* W
5 ^% S1 ?! }4 P7 \) k: E9 _6 w$ P- R. O% ^4 M
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：
7 E$ a! a- ~8 j" e7 N# Y) U4 o57.Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates, _4 f8 c5 Q# b6 W Z
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：
: O% t6 t h7 J; `46. Fidler, I. J. & Kripke, M. L. Metastasis results from preexisting variant cells within a malignant tumor./ f! S6 {/ C# y1 @: s) x
Science 197, 893–895 (1977).
: ^4 l) W4 k3 g47. Fidler, I. J. & Hart, I. R. Biological diversity in metastatic neoplasms: origins and implications. Science
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48.Heppner, G. H. Tumor heterogeneity. Cancer Res. 44, 2259–2265 (1984).
' l, L9 C o n* |. D2 p49.Nowell, P. C. Mechanisms of tumor progression. Cancer Res. 46, 2203–2207 (1986).
) I9 x. D8 e2 A, Y58. Southam, C. M. & Brunschwig, A. Quantitative studies of autotransplantation of human cancer.
; ^9 V" l! P: u* ~Cancer 14, 971–978 (1961).
# L8 k1 U+ _6 r8 J59.Hamburger, A. W. & Salmon, S. E. Primary bioassay of human tumor stem cells. Science 197,) `2 w: m6 q5 @4 y7 N, h) u; @
461–463 (1977).) ~6 ] Y3 E0 A$ d
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# u6 p+ s4 r: { n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：
# o0 \/ d* W5 f3 c9 O% g* ?/ R0 o58. Southam, C. M. & Brunschwig, A. Quantitative studies of autotransplantation of human cancer.
# u7 k7 q1 C5 k$ N$ X8 x: Z" j9 PCancer 14, 971–978 (1961).. |; F( \( P% ~" x
60. Salsbury, A. J. The significance of the circulating cancer cell. Cancer Treatment Rev. 2, 55–72 (1975).
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% ?8 p6 J# s4 ~+ Y: Z7 X4 C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：
! k" }, w/ p, j: T6 S/ [) e45.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：* V: r6 `1 K5 U1 o1 Y- G! O# x" f
61.Williams, S. D. Treatment of disseminated germ cell tumors with cisplatin, bleomycin, and either1 Y0 T: Z6 p/ b* Z) O6 E1 L
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5 Q; t: A( p9 Y. q62. Stockler, M., Wilcken, N. R. C., Ghersi, D. & Simes, R. J. Systematic reviews of chemotherapy and
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63. Lippman, M. E. High-dose chemotherapy plus autologous bone marrow transplantation for
8 V* U" f+ A& emetastatic breast cancer. N. Engl. J. Med. 342, 1119– 1120 (2000).
/ D9 P" f& m3 p7 ?. Q0 ^) J* e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。
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2 J( F+ K1 z& i" I( H8 Q& V7 G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：
: g% M2 m, [$ h! E- P. I0 z: P8 U5 P64.Harrison, D. E. & Lerner, C. P. Most primitive hematopoietic stem cells are stimulated to cycle rapidly
6 `- ?. x: E }after treatment with 5-fluorouracil. Blood 78, 1237– 1240 (1991).& t" m5 J% l1 j+ m, a
这可能时由于该类细胞的抗凋亡蛋白表达水平较高，
) f* }& i' f: q1 k b65.Bouwens, L. & DeBlay, E. Islet morphogenesis and stem cell markers in rat pancreas. J. Histochem.0 B& @) H9 l% Y" y8 d2 X0 D" A
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66.Peters, R., Leyvraz, S. & Perey, L. Apoptotic regulation in primitive hematopoietic precursors. Blood
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l1 {. R1 I& O" c5 {67. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic overexpression of BCL-2 in the hematopoietic system
# [9 A0 `7 P E1 R' ~+ Mprotects transgenic mice from the consequences of lethal irradiation. Blood 91, 2272–2282 (1998).
, V+ I q( Q/ K2 ?) ^- w& S68.Feuerhake, F., Sigg, W., Hofter, E. A., Dimpfl, T. & Welsch, U. Immunohistochemical analysis of Bcl-2
6 C, \ P B4 Land Bax expression in relation to cell turnover and epithelial differentiation markers in the nonlactating
9 a1 D2 b2 _+ j) n( Y9 X# hhuman mammary gland epithelium. Cell Tissue Res. 299, 47 –58 (2000).
# [ L' @7 n9 m- L* r或者由于多药耐药基因等ABC转运体的过表达：0 T1 B" T0 u( ]. I3 V0 [# S
69. Zhou, S. et al. The ABC transporter Bcrp1/ABCG2 is expressed in ; H5 ^/ t; @5 q; s0 R5 W8 p
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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：2 k P" n4 a9 z: U: v. k1 v% y
6. Petersen, B. E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168–1170 (1999).
/ K3 A! a, n8 N3 X& ? |, r2 T/ H7. Brazelton, T. R., Rossi, F. M. V., Keshet, G. I. & Blau, H. M. From marrow to brain: expression of$ e; D7 ~6 }; ?& Z& S3 s$ @7 A
neuronal phenotypes in adult mice. Science 290, 1775– 1779 (2000).
9 z T" [0 Q4 {! ~; {" s8 j8. Mezey, E., Chandross, K. J., Harta, G., Maki, R. A. & McKercher, S. R. Turning blood into brain: cells6 \6 d/ {' |" w' D; W# R' v- R
bearing neuronal antigens generated in vivo from bone marrow. Science 290, 1779–1782 (2000).
5 j) f9 q) k( Q* A0 }: n9. Lagasse, E. et al. Purified hematopoietic stem cells can differentiate to hepatocytes in vivo. Nature# z% @8 I8 p7 u$ {$ N e6 V2 M
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- V Z4 t, b* y2 E& s10.Krause, D. S. et al.Multi-organ, multi-lineage engraftment by a single bone marrow derived stem cell.
6 v, V* j3 e% c0 ECell 105, 369–377 (2001).
4 B% T+ _; G7 B B8 `; D5 F: E6 ~
! }$ v0 B [# d: T! @0 P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：* ~+ N1 K7 [. L* ~
2. Morrison, S. J. & Weissman, I. L. The long-term repopulating subset of hematopoietic stem cells is( @7 l1 |8 ^6 {2 G/ ~
deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).$ M+ s/ {: d7 l3 k
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, D) \" _- N2 s1 F, H9 w5 X/ O造血干细胞的表型和功能特性见以下综述:8 w2 `" L8 f. A% y; v
12.Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities.; b- V, S7 W- R7 T1 O
Science 287, 1442–1446 (2000).
% K: A+ ~6 ?0 X5 V" K! {
* q" }, d$ m4 R+ ~
5 l9 `4 h2 o2 q: l鉴定出保持造血干细胞活性的培养条件：
. L2 z9 j) N7 }- s/ Q/ j13.Miller, C. L. & Eaves, C. J. Expansion in vitro of adult murine hematopoietic stem cells with transplantable
$ Z# B; N/ J8 G1 T0 Y& Plympho-myeloid reconstituting ability. Proc. Natl Acad. Sci. USA 94, 13648–13653 (1997)4 }/ b" B0 r- w @, `
% y- S6 \( ]" `, c5 d4 _. k6 d
; K! M6 `2 Y2 U; F1 W% q
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2：5 z. W% g) ?! b
WNT通路相关肿瘤为结肠癌和上皮肿瘤：
. z- t8 Q; @' l/ o25.Zhu, A. J. & Watt, F. M. b-catenin signalling modulates proliferative potential of human epidermal2 B1 j: x/ C9 \( h" g
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+ d3 c; O, d7 ^2 T1 h23.Austin, T. W., Solar, G. P., Ziegler, F. C., Liem, L. & Matthews, W. A role for the Wnt gene family in
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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：# ~! f( z$ X( r% d: L2 T
19.Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells
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7 P! g; p$ S& L83.Wechsler-Reya, R. & Scott, M. P. The developmental biology of brain tumors. Annu. Rev. Neurosci. 24,
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0 K# x; E4 _6 E5 M1 Y; @3 LNOTCH途径相关肿瘤为T细胞性白血病：: L7 u; g0 _; k- y
17.Varnum-Finney, B. et al. Pluripotent, cytokine- dependent, hematopoietic stem cells are immortalized
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' w) B. q( l& B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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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：
5 X i, I8 l2 o& h75.Sgroi, D. C. et al. In vivo gene expression profile analysis of human breast cancer progression. Cancer% i% E' {" l4 ?8 x) S; k" T- x2 i
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# i" G; S* e2 f; o+ V4 V5 o! B% `
总结：' k9 j, z5 s% a5 B J9 p6 e
1，自我更新是正常组织或肿瘤中干细胞的标志性特点；
" t+ x. Q# \4 w: x6 p! u: L2，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；
# G( H/ y; j. X, a( [8 g, w8 R3，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；: q! t+ y$ f% V
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；
) W! {" n) H }: O% F/ D' }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；
' o, |0 I3 y, ?7 A6，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；
9 \7 I$ ^5 z3 b7 u% r2 o9 j7，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；
% F' O. e5 R+ Q. O. q3 ]! ? q8，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。- \, K, U# I6 U, n+ x
+ P- S2 c3 U0 @9 Q9 T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：9 t' ?- v( l* t. A; O8 t
14. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic overexpression of BCL-2 in the hematopoietic system/ ^5 n9 G4 H3 R
protects transgenic mice from the consequences of lethal irradiation. Blood 91, 2272–2282 (1998).
1 f" S2 V, T3 S! [* z* |15.Domen, J. & Weissman, I. L. Hematopoietic stem cells need two signals to prevent apoptosis; BCL |
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发表于 2009-12-17 10:32
