会“游泳”的细胞

sunsong7

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Weinberg 实验室的博士后研究员Christine Chaffer分析来自人类乳腺组织的细胞，观察到少量的基底细胞在组织培养液中自由漂浮。由于对细胞异常行为的好奇，Chaffer开始着手进一步的研究，将浮动基底细胞注入小鼠。12周后发现注入的基底细胞产生类似于乳管的结构，包含了基底和管腔细胞，这清楚地表明浮动细胞已经去分化至干细胞。
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4 b0 m8 r9 o" S/ `这些结果不但挑战了细胞分化单向性，而且揭示了细胞摆脱失巢凋亡后的命运。
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. t  o# u* o- A; W8 K成体干细胞必须住在niche中，一旦离开了niche就启动了不对称分裂，他们的后代有一般两条路可走：一个方向分化成终末成熟细胞呈现功能化，最终命运指向死亡；另一个方向就是归巢，干细胞回到niche里睡大觉（G0）。那么，如果干细胞离巢后出现在非预期微环境中忘记了回家的路，将会发生什么呢？
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1 T1 b9 r8 a5 {" H+ X4 v6 C( g一般说来等待无家可归干细胞的命运就是失巢凋亡。失巢的干细胞就像是被遗弃的婴儿，幸运的孩子往往会遇上好心人将其带回家抚养成人，没人捡到的婴儿“恐怕”必死无疑的....之所以这里用了“恐怕”是因为大自然能创造出各种“意外”，因为现实生活中有“狼孩”故事的奇迹发生。+ R+ n. t+ \' M% X$ m2 \( Y- ]
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失巢的干细胞偶然的机会在non-niche微环境中生存下来了，正如上文所述，基底细胞放弃了贴壁生长的本性却学会了“游泳”。环境改变命运，类似的现象在生物进化过程中有许多案例，哺乳动物“偶然”练就潜泳的本领适应水中长期生活方式，譬如海豹、鲸鱼...7 L0 e- `% c; O5 S: g' [

2 j) m& M$ j1 a" {想一想，哪些细胞会游泳： 血细胞、淋巴细胞、精子、卵子、胚胎干细胞、肿瘤细胞....这是巧合吗？
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9 q) ^# f4 t" I【相关术语】) i( m7 {" I' @2 p1 B/ k
细胞凋亡(apoptosis )：体细胞在特定的内源和外源信号诱导下，其死亡途径被激活，并在有关基因的调控下发生的程序性死亡过程。/ f" k3 M! J" v$ H
失巢凋亡（anoikis: suspension-induced apoptosis)：正常的贴壁细胞如果长时间处于悬浮状态就会死亡。是一种形式的细胞程序死亡，是由与细胞外基质和其他细胞脱离接触而诱发的。
; W3 Y6 ~4 R! {9 D接触抑制（contact inhibition ）：将多细胞生物的细胞进行体外培养时，分散贴壁生长的细胞一旦相互汇合接触，即停止移动和生长的现象。$ @8 O* S. w+ U* b( Z% e
贴壁生长（growth of adherent ）：大多数正常真核细胞只有在黏附于一定的细胞外基质时才能生长（包括存活及进入细胞增殖周期），具有贴附和伸展以及接触抑制和生长的密度限制。一般来说，从底物脱离下来的贴附生长型细胞，不能长期在悬浮中生长而将逐渐退变，除非这是一些转化了的细胞或恶性肿瘤细胞。
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$ C5 _- m$ a( l2 j【扩展阅读】
2 e  s  \/ j: cPNAS:科学家发现肿瘤干细胞的一种新来源 http://www.stemcell8.cn/thread-38025-1-1.html  ?  L# C6 b! A& a  J  A+ }2 J: t
脱落凋亡，细胞死于思乡病 http://www.stemcell8.cn/thread-39627-1-1.html
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xiao6tao

有没有原文  很干兴趣

sunsong7

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0 Q* T) V3 r+ F, }9 b& t- o回复 xiao6tao 的帖子8 Q  ?3 B. d! w: E. h- m

3 w2 I& J1 @. [: C8 G( U“失巢凋亡”的发现：据美国《Scientist》介绍，美国加州的Scripps Research Institute 的Martin Schwartz在上世纪的90年代初的某天，无意中犯了一个错误，误将内皮细胞悬浮过夜培养，第二天，他才意识到自己犯了一个错误，细胞都死翘翘啦，但他敏锐的发现这些死细胞都有类似于细胞凋亡引起的水泡状。Schwartz就进一步研究其机理，文章发在MOLECULAR BIOLOGY OF THE CELL ，自1993年发表以来，迄今该文已被引用超过1000次。
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sunsong7

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体细胞从去分化到癌变的故事：前述Christine Chaffer分离出会“游泳”的基底细胞不但能够自发地恢复到干细胞状态，Chaffer又将致癌基因注入到这些细胞中，之后被注入到小鼠中，发现小鼠体内的肿瘤中含有癌症干细胞群，它们是原先基底细胞的后裔。这一结果表明乳腺癌肿瘤中的基底细胞是癌症干细胞中一个先前未知的来源，他们揭示出，正常来源细胞所处的分化状态在很大程度上决定了转化后细胞的行为方式。

sunsong7

失巢凋亡相关综述：作为一种特殊的程序化细胞死亡形式，在机体发育、组织自身平衡、疾病发生和肿瘤转移中起重要作用。对失巢凋亡的深入研究，逐步揭示了其分子机制。失巢凋亡通过传统的细胞凋亡途径诱导细胞死亡。整合蛋白感知和传导细胞外基质信号而控制细胞的粘附和存活，Bcl-2和某些Bcl-2相关蛋白广泛参与细胞失巢凋亡的调节，多种蛋白激酶信号分子参与失巢凋亡的信号转导。近期研究揭示了一种抑制失巢凋亡和诱导肿瘤转移的蛋白称作TrkB，为失巢凋亡抑制与肿瘤恶性浸润性的关系提供了实验依据。' d% i0 P. e1 G

sunsong7

【失巢凋亡】 Anoikis0 x9 b7 r# A" o5 I
From Wikipedia, the free encyclopedia  http://en.wikipedia.org/wiki/Anoikis
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Anoikis is a form of programmed cell death which is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix (ECM).[1] Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival. When cells are detached from the ECM, i.e. there is a loss of normal cell–matrix interactions, they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.
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2 P& r6 v0 J* e& M# k% q Etymology : s' o5 @8 c7 q$ P& a
The word Anoikis was coined by Frisch and Francis in a paper published in the Journal of Cell Biology in 1994. Anoikis, in their words, means "(...the state of being without a home) to describe the cells' apoptotic response to the absence of cell–matrix interactions." The word apparently is a Neolatin construction consisting of three Greek morphemes agglutinated together: ἀν- "without", οἰκ- "house", and -ις (extracted from -σις "trait, attribute"; confer apo-pto-sis "state of being fallen off").0 @/ z- z+ ?1 [4 s/ a" U
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Anoikis in metastasis
$ o& C- o/ @  v' e$ N' NThe mechanism by which invading tumor cells survive the anoikis process remains largely unknown. Recent findings suggest that the protein TrkB, best known for its role in the nervous system, might be involved together with its ligand, brain-derived neurotrophic factor (BDNF). It seems that TrkB could make tumor cells resistant to anoikis by activating phosphatidylinositol 3-kinase (PI3K) signaling cascade. In squamous cell carcinoma, researchers have found that anoikis resistance can be induced through hepatocyte growth factor (HGF) activating BOTH extracellular signalling-receptor kinase (ERK) and PI3K.
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  f0 k5 N7 V! r8 a# {2 ]Using a novel high-throughput screening assay, Mawji et al. showed that anisomycin can sensitize metastatic epithelial cells to anoikis and reduce circulating tumor cell implantation in vivo.[2] Anisomycin achieved this anti-metastatic activity in part by decreasing the abundance of the death receptor inhibiting protein FLIP. In related work, Schimmer's team showed that FLIP levels are higher in metastatic cells than non-metastatic cells, and that reducing FLIP levels using RNAi (RNA Interference) or other small molecule inhibitors of FLIP can sensitize metastatic cells to anoikis.[3] Given that FLIP is an inhibitor of anoikis, and that reducing FLIP can sensitize metastatic cells to anoikis, Mawji et al hypothesize that FLIP reduction may be a viable therapeutic strategy against cancer metastasis.# \* p% v; I! n: I, p6 V) Z; q$ C
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References
. O- t$ V! Q* d( {) ~, r& o Frisch SM, Screaton RA (October 2001). "Anoikis mechanisms". Current Opinion in Cell Biology 13 (5): 555–62. doi:10.1016/S0955-0674(00)00251-9. PMID 11544023.  2 n4 w( L2 |1 Q: N1 w, V
Mawji IA, Simpson CD, Gronda M, et al. (September 2007). "A chemical screen identifies anisomycin as an anoikis sensitizer that functions by decreasing FLIP protein synthesis". Cancer Research 67 (17): 8307–15. doi:10.1158/0008-5472.CAN-07-1687. PMID 17804746.  
- I- y7 T6 d( `2 B Mawji IA, Simpson CD, Hurren R, et al. (May 2007). "Critical role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation". Journal of the National Cancer Institute 99 (10): 811–22. doi:10.1093/jnci/djk182. PMID 17505076.  
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Further reading * Y- G/ ?* M& `* q3 j  A6 s
Frisch SM, Francis H (February 1994). "Disruption of epithelial cell-matrix interactions induces apoptosis". The Journal of Cell Biology 124 (4): 619–26. doi:10.1083/jcb.124.4.619. PMC 2119917. PMID 8106557. http://www.jcb.org/cgi/pmidlookup?view=long&pmid=8106557.    d. k3 Y3 z9 D% ~2 O+ N! ?# S
Liotta LA, Kohn E (August 2004). "Anoikis: cancer and the homeless cell". Nature 430 (7003): 973–4. doi:10.1038/430973a. PMID 15329701.  # v; p0 u# Y) e
Zeng Q, Chen S, You Z, et al. (July 2002). "Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B". The Journal of Biological Chemistry 277 (28): 25203–8. doi:10.1074/jbc.M201598200. PMID 11994287.  * E1 B* \; G& G/ B! ]0 q
Retrieved from "http://en.wikipedia.org/wiki/Anoikis"* v  r* O+ Q; g' ]
Categories: Programmed cell death | Apoptosis

sunsong7

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失巢凋亡是贴壁依赖细胞（anchorage-dependent cells）从周围的细胞外基质（ extracellular matrix，ECM）脱落后引起的程序性死亡。ECM某种程度上就是通常意义上的细胞微环境（microenvironment）。
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由于细胞与细胞之间、细胞邻近组织细胞之间、以及细胞与为其提供必要的生长信号或生存条件的细胞外基质之间需要保持通讯联系，通常细胞要需要与所属组织保持密切接触。当细胞从细胞外基质中游离出来，细胞失去了与细胞基质的相互作用就会发生失巢凋亡。
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简单地说，当细胞离开了它赖以生存的微环境可能会因“孤独”而死亡。但是，如果细胞练就了“游泳”的本领情况就将大不相同，会“游泳”的细胞拥有了更大的生存能力和发展空间，它们还恢复了干细胞的多能性，老狼暂且把这种现象称作“失巣新生（suspension-induced palingenesis）”。
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更进一步，如果会“游泳”的细胞长期流浪彻底摆脱了失巢凋亡的魔咒将会发生什么呢？会不会发生“失巣永生（suspension-induced immortalization）”呢？  事实上，转移性肿瘤细胞就逃脱了失巢凋亡的命运，它们获得了侵袭其他组织器官的能力。
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sunsong7

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会“游泳”的细胞相关阅读：
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  f$ P' N' n1 D- X% I8 B5 D( s“上皮细胞基质相互作用瓦解引起失巢凋亡”  Frisch SM, Francis H (February 1994). "Disruption of epithelial cell-matrix interactions induces apoptosis". The Journal of Cell Biology 124 (4): 619–26. doi:10.1083/jcb.124.4.619. PMC 2119917. PMID 8106557. http://www.jcb.org/cgi/pmidlookup?view=long&pmid=8106557.  ) c$ N3 ?; x: m, b" z9 {
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“力传导与失巣凋亡：死亡与无家可归的细胞” Zhenyi Ma, Zhe Liu, David P. Myers, and Lance S. Terada “Mechanotransduction and anoikis: Death and the homeless cell”.Cell Cycle. 2008 August 15; 7(16): 2462–2465! W7 ~$ Z( O7 D7 [
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“失巢凋亡：癌与无家可归细胞” Liotta LA, Kohn E (August 2004). "Anoikis: cancer and the homeless cell". Nature 430 (7003): 973–4. doi:10.1038/430973a. PMID 15329701.  
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8 X# z" ]( o% M' m4 m+ W" h1 g8 t. oLive Free or Die. Tales of Homeless (Cells) in Cancer. （自由还是死亡：癌的无家可归故事）
7 r: s" r& X; w, G9 CHome » Latest PubMed Articles » Live Free or Die. Tales of Homeless (Cells) in Cancer.0 y+ }0 Q$ |3 [' v5 L; s7 ~
Summary7 F! i& P  Y! n7 e4 B
Anoikis, programed cell death that occurs on cell detachment from the extracellular matrix, thus disrupting integrin-ligand interactions, is a critical mechanism in preventing ectopic cell growth or attachment to an inappropriate matrix. Anoikis prevents shed epithelial cells from colonizing elsewhere and is thus essential for maintaining tissue organization. Lack of integrin ligation leads to decreased focal adhesion kinase and integrin-linked kinase activity, which impairs downstream survival signaling. Consequently, targeting tumor cell survival by triggering anoikis provides a unique molecular basis for novel therapeutic targeting of tumors before initiation of metastasis. The two major cell death pathways involved in anoikis signaling are apoptosis and autophagy; growing evidence suggests an extensive cross-talk between the two killing modes as well as context-dependent cooperation and antagonism. This review discusses the functional integration between the two modes of cell death converging at anoikis, including key molecules of interaction such as Beclin 1, reactive oxygen species, extracellular signal-related kinase, and death-associated protein kinase. The involvement of other apoptotic effectors such as Bcl-2, p53, and FLICE inhibitory protein in cancer cell anoikis is also discussed. Dissecting the mechanistic players in the cellular response may be of high clinical significance in identifying effective approaches in reversing anoikis resistance in primary tumor cells and, consequently, impairing metastasis.+ l. g/ [- f9 S1 N, Z! b
Affiliation:  From the Departments of Pathology,* Surgery/Urology, and Molecular Biochemistry, University of Kentucky, Lexington, Kentucky.  H4 c& |7 o; r1 b" N
Journal : The American journal of pathology  ISSN: 1525-2191  http://www.bioportfolio.com/reso ... ells-In-Cancer.html
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marrowstem

建议贴上“Live Free or Die. Tales of Homeless (Cells) in Cancer. （自由还是死亡：癌的无家可归故事）”全文。0 r+ k+ {3 t; ]& p
不胜感激！
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sunsong7

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) }. o8 i8 Z: S+ HLive Free or Die:Tales of Homeless (Cells) in Cancer  全文需要付费下载
3 D5 W7 p$ i, t$ q9 y: }$ BThe American Journal of Pathology  Volume 177, Issue 3 , Pages 1044-1052, September 2010.  http://www.journals.elsevierheal ... 10)60159-9/abstract