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 - 肿瘤干细胞专区干细胞之家



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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：

http://mcardle.oncology.wisc.edu/alexander/PDF/Reya.pdf

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。

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：
35. Lagasse, E. & Weissman, I. L. bcl-2 inhibits    apoptosis of neutrophils but not their engulfment by
macrophages. J. Exp. Med. 179, 1047–1052 (1994).' Y: g6 S! c; ~: A+ C
36.Traver, D., Akashi, K., Weissman, I. L. & Lagasse, E.    Mice defective in two apoptosis pathways in the( a$ V7 {; _  S" u, \" x
myeloid lineage develop acute myeloblastic leukemia.    Immunity 9, 47–57 (1998).

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：7 h& \  _% d0 t% w
37.Polakis, P. Wnt signaling and cancer. Genes Dev. 14,    1837–1851 (2000).
38.Tsukamoto, A., Grosschedl, R., Guzman, R., Parslow,    T. & Varmus, H. E. Expression of the int-1 gene
in transgenic mice is associated with mammary gland    hyperplasia and adenocarcinomas in male and
female mice. Cell 55, 619–625 (1988).
$ f/ H1 ], Y- Q

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：
12.Weissman, I. L. Translating stem and progenitor cell    biology to the clinic: barriers and opportunities.
Science 287, 1442–1446 (2000).
44.Morrison, S. J., Shah, N. M. & Anderson, D. J.    Regulatory mechanisms in stem cell biology. Cell 88,
287–298 (1997).  D+ I' M& r' z7 D! M
45.Kummermehr, J. & Trott, K.-R. in Stem Cells (ed.    Potten, C. S.) 363–399 (Academic, New York, 1997).
( u7 Y2 U1 k( u0 H1 y5 B
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：, H& c- w4 B" `, _. [- U
53.Park, C. H., Bergsagel, D. E. & McCulloch, E. A.    Mouse myeloma tumor stem cells: a primary cell
culture assay. J. Natl Cancer Inst. 46, 411–422 (1971).
54.Bruce, W. R. & Gaag, H. v. d. A quantitative assay    for the number of murine lymphoma cells capable
of proliferation in vivo. Nature 199, 79–80 (1963).
55.Wodinsky, I., Swiniarski, J. & Kensler, C. J. Spleen    colony studies of leukemia L1210. I. Growth8 ?5 z% q+ _1 \$ V- P! N. H
kinetics of lymphocytic L1210 cells in vivo as    determined by spleen colony assay. Cancer Chemother.. J+ G2 K; u1 ?2 U9 p8 u
Rep. 51, 415–421 (1967).; g4 B6 g, ?1 M. _
56.Bergsagel, D. E. & Valeriote, F. A. Growth    characteristics of a mouse plasma cell tumor. Cancer    Res. 28,
2187–2196 (1968).5 n3 l7 p) G  Y2 q4 K
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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：/ @/ }' ]; E! V8 _9 v
57.Bonnet, D. & Dick, J. E. Human acute myeloid leukemia    is organized as a hierarchy that originates8 e' J0 P& {# f# @" ~
from a primitive hematopoietic cell. Nature Med. 3, 730 –737 (1997).
8 m! C3 V5 E' Z" {2 f! w

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" \& ^, e1 x  ^9 s  {/ F% \* P/ C
46. Fidler, I. J. & Kripke, M. L. Metastasis results    from preexisting variant cells within a malignant tumor.! n2 U# _  R, K
Science 197, 893–895 (1977).
47. Fidler, I. J. & Hart, I. R. Biological diversity in    metastatic neoplasms: origins and implications. Science
217, 998–1003 (1982).
48.Heppner, G. H. Tumor heterogeneity. Cancer Res. 44,    2259–2265 (1984).
49.Nowell, P. C. Mechanisms of tumor progression. Cancer    Res. 46, 2203–2207 (1986).* C: N- H# o4 g4 D2 ^- G: R
58. Southam, C. M. & Brunschwig, A. Quantitative studies    of autotransplantation of human cancer.( e4 |8 I, z& L; k- m
Cancer 14, 971–978 (1961).9 u. g8 }# m3 r/ {1 K3 b
59.Hamburger, A. W. & Salmon, S. E. Primary bioassay of    human tumor stem cells. Science 197,# [3 \+ S. m# h8 \: c5 u
461–463 (1977).* [$ h2 `& d% W" T2 ?- ~

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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：
58. Southam, C. M. & Brunschwig, A. Quantitative studies    of autotransplantation of human cancer.# c& m0 L8 v5 A6 o8 ^% l
Cancer 14, 971–978 (1961).4 p; w$ b1 o! a) g2 V) }6 `
60. Salsbury, A. J. The significance of the circulating    cancer cell. Cancer Treatment Rev. 2, 55–72 (1975).1 B% a# X  Q: O# R

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：
45.Kummermehr, J. & Trott, K.-R. in Stem Cells (ed.    Potten, C. S.) 363–399 (Academic, New York, 1997).
" a2 ~- \, R) G$ C" H) T

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：3 r% D( n0 u8 m* R
61.Williams, S. D. Treatment of disseminated germ cell    tumors with cisplatin, bleomycin, and either  F' u" ?& [7 R3 ?; y. h9 _
vinblastine or etoposide. N. Engl. J. Med. 316, 1435– 1439 (1987).5 T& {% i# J9 B. z2 {- D
62. Stockler, M., Wilcken, N. R. C., Ghersi, D. & Simes,    R. J. Systematic reviews of chemotherapy and# s: ~5 V' A: e3 F6 o1 F3 G
endocrine therapy in metastatic breast cancer. Cancer    Treatment Rev. 26, 151–168 (2000).
63. Lippman, M. E. High-dose chemotherapy plus    autologous bone marrow transplantation for
metastatic breast cancer. N. Engl. J. Med. 342, 1119– 1120 (2000).$ A5 R0 q6 V0 P! ^6 w
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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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：, w5 n4 j4 v9 ?. Q$ @
64.Harrison, D. E. & Lerner, C. P. Most primitive    hematopoietic stem cells are stimulated to cycle rapidly$ D+ u& s2 u& ?0 H( Z7 U$ D# n: H
after treatment with 5-fluorouracil. Blood 78, 1237– 1240 (1991).0 l9 {# p3 S. c! W* n
这可能时由于该类细胞的抗凋亡蛋白表达水平较高，
65.Bouwens, L. & DeBlay, E. Islet morphogenesis and stem    cell markers in rat pancreas. J. Histochem.) J- d, {2 _( v( R4 y! w- f/ K- M* }
Cytochem. 44, 947–951 (1996).
66.Peters, R., Leyvraz, S. & Perey, L. Apoptotic    regulation in primitive hematopoietic precursors. Blood+ Q$ p  a! U8 u; P5 J" C- |
92, 2041–2052 (1998).4 B; `% K/ v6 A0 c+ [
67. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic    overexpression of BCL-2 in the hematopoietic system
protects transgenic mice from the consequences of lethal    irradiation. Blood 91, 2272–2282 (1998).
68.Feuerhake, F., Sigg, W., Hofter, E. A., Dimpfl, T. &    Welsch, U. Immunohistochemical analysis of Bcl-21 F& b: B1 U# w4 N
and Bax expression in relation to cell turnover and    epithelial differentiation markers in the nonlactating, Q5 Y$ j: }5 ^- l+ j" L
human mammary gland epithelium. Cell Tissue Res. 299, 47 –58 (2000).
或者由于多药耐药基因等ABC转运体的过表达：+ p  a3 Y4 `  ?5 J1 z& g; H
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：
6. Petersen, B. E. et al. Bone marrow as a potential    source of hepatic oval cells. Science 284, 1168–1170    (1999).' t% t! C6 ^4 s0 O* h
7. Brazelton, T. R., Rossi, F. M. V., Keshet, G. I. &    Blau, H. M. From marrow to brain: expression of: j; H$ C0 q9 S9 |7 \% w, S
neuronal phenotypes in adult mice. Science 290, 1775– 1779 (2000).
8. Mezey, E., Chandross, K. J., Harta, G., Maki, R. A. &    McKercher, S. R. Turning blood into brain: cells
bearing neuronal antigens generated in vivo from bone    marrow. Science 290, 1779–1782 (2000).5 \) i  r" Z5 C! U
9. Lagasse, E. et al. Purified hematopoietic stem cells    can differentiate to hepatocytes in vivo. Nature& x" j; }9 ?( L+ U
Med. 6, 1229–1234 (2000).# g' j3 t' h  g" Z6 H
10.Krause, D. S. et al.Multi-organ, multi-lineage    engraftment by a single bone marrow derived stem cell.3 f% Q- [. Y' q
Cell 105, 369–377 (2001).# W7 a! r% l* n) c* \+ B, O. E
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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：
2. Morrison, S. J. & Weissman, I. L. The long-term    repopulating subset of hematopoietic stem cells is  c* S7 I. k$ p' T$ U3 y
deterministic and isolatable by phenotype. Immunity 1,    661–673 (1994).
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11.Morrison, S. J., Wandycz, A. M., Hemmati, H. D.,    Wright, D. E. & Weissman, I. L. Identification of a
lineage of multipotent hematopoietic progenitors.    Development 124, 1929–1939 (1997).& A% e; I* Q+ C5 G5 O! H
* s8 p/ O7 T7 h& I! J5 ]7 I/ z, {# a) S

造血干细胞的表型和功能特性见以下综述:, k7 f# Q2 ]& Z+ k$ B: R8 b9 N: }
12.Weissman, I. L. Translating stem and progenitor cell    biology to the clinic: barriers and opportunities.
Science 287, 1442–1446 (2000).
& v5 R8 J  W/ m1 R1 V: m

鉴定出保持造血干细胞活性的培养条件：
13.Miller, C. L. & Eaves, C. J. Expansion in vitro of    adult murine hematopoietic stem cells with    transplantable
lympho-myeloid reconstituting ability. Proc. Natl Acad.    Sci. USA 94, 13648–13653 (1997): E% o( i4 H6 I# [% r
4 q: C' v+ o2 Z- g8 U+ Y

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：" _- M4 A: h* W! c- D
WNT通路相关肿瘤为结肠癌和上皮肿瘤：
25.Zhu, A. J. & Watt, F. M. b-catenin signalling    modulates proliferative potential of human epidermal
keratinocytes independently of intercellular adhesion.    Development 126, 2285–2298 (1999).# X. M+ n3 t) |  K  |6 b( U
27.Korinek, V. et al. Depletion of epithelia stem-cell    compartments in the small intestine of mice lacking# l2 D. \3 t  |. z) z) t: ?( f
Tcf-4. Nature Genet. 19, 1–5 (1998).
37.Polakis, P. Wnt signaling and cancer. Genes Dev. 14,    1837–1851 (2000).) w! W5 u2 u% V9 k7 g. s( M/ v; G: B0 F
82. Chan, E. F., Gat, U., McNiff, J. M. & Fuchs, E. A    common human skin tumour is caused by activating
mutations in b-catenin. Nature Genet. 21, 410–413    (1999).5 z/ q% o+ x% ]& {& E0 j  j
20.Nusse, R. & Varmus, H. E. Many tumors induced by the    mouse mammary tumor virus contain a
provirus integrated in the same region of the host    genome. Cell 31, 99–109 (1982).
21. Cadigan, K. M. & Nusse, R. Wnt signaling: a common    theme in animal development. Genes Dev. 11,
3286–3305 (1997).7 \* `$ D. o& M/ Q1 ?8 m' x+ P
22.Reya, T. et al. Wnt signaling regulates B lymphocyte    proliferation through a LEF-1 dependent
mechanism. Immunity 13, 15–24 (2000)., C. P% J. ?3 m
23.Austin, T. W., Solar, G. P., Ziegler, F. C., Liem, L.    & Matthews, W. A role for the Wnt gene family in$ w8 @: o4 p4 T% `4 e6 c
hematopoiesis: expansion of multilineage progenitor    cells. Blood 89, 3624–3635 (1997).
24.Van Den Berg, D. J., Sharma, A. K., Bruno, E. &    Hoffman, R. Role of members of the Wnt gene family
in human hematopoiesis. Blood 92, 3189–3202 (1998).9 u# D$ g2 \; D
26. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De    novo hair follicle morphogenesis and hair
tumors in mice expressing a truncated b-catenin in skin.    Cell 95, 605–614 (1998).8 S% f) B( B" p( v; C' [  ]' h: K9 O6 X

SHH途径相关肿瘤为成神经管细胞瘤和基底细胞癌：  H" L$ u9 z2 _! j9 t2 |) h
19.Bhardwaj, G. et al. Sonic hedgehog induces the    proliferation of primitive human hematopoietic cells' {9 K& k: s, ~2 h! O5 |, G1 A
via BMP regulation. Nature Immunol. 2, 172–180 (2001)./ r% Y) ]! f% @8 |6 ~" d
78.Wechsler-Reya, R. J. & Scott, M. P. Control of    neuronal precursor proliferation in the cerebellum by* f( p. Y6 |, d0 S; L* T! s
Sonic Hedgehog. Neuron 22, 103–114 (1999).
79.Zhang, Y. & Kalderon, D. Hedgehog acts as a somatic    stem cell factor in the Drosophila ovary. Nature4 S4 D% i; J9 f; ]0 b
410, 599–604 (2001).& B8 I* ^' H6 z/ ]+ g
83.Wechsler-Reya, R. & Scott, M. P. The developmental    biology of brain tumors. Annu. Rev. Neurosci. 24,
385–428 (2001).
84. Gailani, M. R. & Bale, A. E. Acquired and inherited    basal cell carcinomas and the patched gene. Adv.- }9 \2 I. b7 F" V7 u) ^: S% G
Dermatol. 14, 261–283 (1999).
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NOTCH途径相关肿瘤为T细胞性白血病：
17.Varnum-Finney, B. et al. Pluripotent, cytokine- dependent, hematopoietic stem cells are immortalized7 @9 c0 u' u3 e' i' T* k
by constitutive Notch1 signaling. Nature Med. 6, 1278– 1281 (2000).9 d6 y) n% z4 M# D
80.Henrique, D. et al.Maintenance of neuroepithelial    progenitor cells by Delta-Notch signalling in the! K$ F% z3 N: o. ]5 _+ a; J% z# e
embryonic chick retina. Curr. Biol. 7, 661–670 (1997).
81.Austin, J. & Kimble, J. glp-1 is required in the germ    line for regulation of the decision between mitosis
and meiosis in C. elegans. Cell 51, 589–599 (1987).- O: I+ A; P) ]" k3 j
85. Ellisen, L. W. et al. TAN-1, the human homolog of    the Drosophila notch gene, is broken by
chromosomal translocations in T lymphoblastic neoplasms.    Cell 66, 649–661 (1991).
; r( U) j- B% k# l6 X$ D. N
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：
71.Bittner, M. et al.Molecular classification of    cutaneous malignant melanoma by gene expression4 n: G4 |, Q$ I' e6 P! v: V: c3 v
profiling. Nature 406, 536–540 (2000).
72.Perou, C. M. et al.Molecular portraits of human    breast tumours. Nature 406, 747–752 (2000).% ]' h) q. G% x9 Q+ D8 n" \1 I
73. Alizadeh, A. A. et al. Distinct types of diffuse    large B-cell lymphoma identified by gene expression
profiling. Nature 403, 503–511 (2000).
74.Golub, T. R. Genome-wide views of cancer. N. Engl. J.    Med. 344, 601–602 (2001).

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：
75.Sgroi, D. C. et al. In vivo gene expression profile    analysis of human breast cancer progression. Cancer+ p$ `) g2 [$ |% ]$ ]4 L4 S1 p
Res. 59, 5656–5661 (1999).- T0 g5 q: T* k
76.Leethanakul, C. et al. Distinct pattern of expression    of differentiation and growth-related genes in
squamous cell carcinomas of the head and neck revealed    by the use of laser capture microdissection0 s( J% {8 H% d( M( H0 x' O
and cDNA arrays. Oncogene 19, 3220–3224 (2000)./ D% u  E4 U4 A6 U

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总结：
1，自我更新是正常组织或肿瘤中干细胞的标志性特点；
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；1 E5 \) p+ |+ o2 L! n5 u* _
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；
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；  D' x8 I, b. j- A
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；
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；! M* w* W8 M$ q. y$ ^$ H# g
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；
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。

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：4 ?9 m. \9 E8 D3 x. L* ]
14. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic    overexpression of BCL-2 in the hematopoietic system
protects transgenic mice from the consequences of lethal    irradiation. Blood 91, 2272–2282 (1998).9 }& e  W7 ?3 {
15.Domen, J. & Weissman, I. L. Hematopoietic stem cells    need two signals to prevent apoptosis; BCL

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