肿瘤细胞起源的新视角（ZT）

marrowstem

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       ６月２４日的《Cell》杂志发表了一篇由哈佛大学细胞生物学教授写的论文，从新的角度探索了致死性肿瘤的细胞起源，令人眼睛为之一亮；与（几十年来由癌症研究所形成的）肿瘤源自细胞遗传学改变这一经典观念不同，研究者发现发育早期遗留的少许胚胎细胞在一定条件下会被快速诱导为肿瘤前体细胞；这一非同寻常的机制对治疗致死性肿瘤有非同寻常的意义：为单克隆抗体与小分子抑制剂双双提供了关键靶标！
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marrowstem

哈佛大学的报道全文：　　　! t- \' e; A$ R% A8 t
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New Insights into Origin of Deadly Cancer$ b* W0 |/ C( e. _  }3 W
June 23, 2011
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      Barrett’s esophagus, often a precursor to esophageal cancer, results from residual, embryonic cells.
  e% r. d4 @( s6 N  N% E) X       Researchers have discovered a new mechanism for the origin of Barrett’s esophagus, an intestine-like growth in the esophagus that is triggered by chronic acid reflux and often progresses to esophageal cancer. Studying mice, the researchers found that Barrett’s esophagus arises not from mutant cells in the esophagus but rather a small group of previously overlooked cells present in all adults that can rapidly expand to cancer precursors when the normal esophagus is damaged by acid.4 Y7 q3 d0 A* n
     This research will be published online in the June 24th issue of Cell.9 k- ?8 u2 P$ T. j; Z3 l; K, i
      Decades of cancer research tells us that most of the common cancers begin with genetic changes that occur over a period of 15 to 20 years, in some cases leading to aggressive cancers. However, for a subset of cancers that appear to be linked to chronic inflammation, this model might not hold./ D: S+ \* c) ?  t( `+ s! \
       Barrett’s esophagus, which was first described by the Australian surgeon Norman Barrett in 1950, affects two to four million Americans. In this condition, tissue forms in the esophagus that resembles the intestinal tissue normally located much farther down the digestive tract. As a result, a person’s chances of developing a deadly esophageal adenocarcinoma increase by 50- to 150-fold. Late stage treatment is largely palliative, so it is important to understand how acid reflux triggers it in the first place.
4 o! h5 a8 O- f! r1 ^9 F. a& I       Research from the laboratory of Frank McKeon, Harvard Medical School professor of cell biology, together with Wa Xian, a postdoctoral researcher at Brigham and Women’s Hospital and the Institute of Medical Biology, Singapore, along with an international consortium including Christopher Crum, director of Women’s and Perinatal Pathology at Brigham and Women’s Hospital, has shown that Barrett’s esophagus originates from a minor population of non-esophageal cells left over from early development.
6 w8 o% v( c# E- ^: X$ e2 [" R$ F% h        For the past decade, McKeon and his laboratory have been using mouse models to investigate the role of p63, a gene involved in the self-renewal of epithelial stem cells including those of the esophagus. McKeon joined forces two years ago with Wa Xian, an expert in signal transduction in cancer cells, to tackle the vexing problem of the origin of Barrett’s esophagus.
2 g* a* i% V7 G         At that time, the dominant hypothesis for Barrett’s was that acid reflux triggers the esophageal stem cells to make intestine cells rather than normal esophageal tissue. However, McKeon and Xian felt the support for this concept was weak. Taking a different track, they studied a mouse mutant lacking the p63 gene and mimicked the symptoms of acid reflux. As a result, the entire esophagus was covered with a Barrett’s-like tissue that proved to be a near exact match with human Barrett’s at the gene expression level.% R( w% O' r8 F& B
          The researchers were particularly surprised by the sheer speed with which this Barrett’s esophagus appeared in the mice.
' X& g8 `' Y- K2 ~$ C- f         “From the speed alone we knew we were dealing with something different here,” said Xia Wang, postdoctoral fellow at Harvard Medical School and co-first author of this work.7 z& g  _8 ]# o% [( g' E
             Yusuke Yamamoto, a postdoctoral fellow at the Genome Institute of Singapore and also co-first author, added that, “we just had to track the origins of the Barrett’s cells back through embryogenesis using our markers from extensive bioinformatics.”
; f. [8 r( \0 o2 A+ X; @8 ]      In essence, the investigators tracked the precancerous growth to a discrete group of leftover embryonic cells wedged between the junction of the esophagus and the stomach–precisely where endoscopists have argued Barrett’s esophagus begins. As predicted by the mouse studies, the researchers identified a group of embryonic cells exactly at the junction between the esophagus and the stomach in all normal humans. $ J; Z+ \3 ^2 ~# b2 t  Z
        “Barrett’s arises from this discrete group of pre-existing, residual embryonic cells present in all adults that seemingly lie-in-wait for a chance to take over when the esophagus is damaged,” said McKeon. Added Xian, “We know these embryonic cells have different gene expression patterns from all normal tissues and this makes them inviting targets for therapies to destroy Barrett’s before it progresses to cancer.”
0 {- g, |9 N: a4 h4 b' Y, ~% d) `" O      The therapeutic opportunities of this work are potentially immense.
2 c  p1 `  d( V  d% D( N: P      “We are directing monoclonal antibodies to cell surface markers that can identify these precursor cells, so we may have a new opportunity to intervene therapeutically and prevent Barrett’s esophagus in at-risk patients,” said Wa Xian.6 g  H$ t# {; ]1 F7 x
       “Additionally,” noted McKeon, “we are cloning the stem cells for both these precursors and for Barrett’s esophagus itself, and these should represent critical targets for both monoclonal antibodies and small molecule inhibitors.”$ l  t- p: q; X6 }8 x8 \
          Finally, there is reason to believe that this unusual mechanism might apply to a subset of other lethal cancers with unsure origins.8 O5 I, s: Z1 m  a
         Crum noted that “some very aggressive cancers arise at junctions of two tissues and these deserve closer scrutiny to get at their origins if we are to surmount these diseases.”
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sunsong7

机体组织中普遍存在着不同级别可塑性细胞，包括所谓的亚全能干细胞、vsel，muse等万能细胞（pluripotent stem cells），另一方面文中所述的胚胎残留细胞（residual embryonic cells）应该属于也“万能干细胞”；另外，机体所有组织都来源于胚胎干细胞，说这些源自于胚胎残留缺乏依据；

marrowstem

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7 c; e* V5 ~3 ~" O& c回复 sunsong7 的帖子3 y- v+ c9 ]  {) U

% n9 r% Z' e1 U9 \问狼兄：
- E$ X2 C* l+ j- {) a% Y    你定义的万能干细胞有多万能？人体中细胞种类可只有200多种，比“万能”少了九千八百种。我觉得应该定义百能干细胞为妥！

marrowstem

可含三胚层组织结构的畸胎瘤的瘤细胞起始源自何处？

sunsong7

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marrowstem 发表于 2011-6-30 16:41 $ [5 l5 m" K$ c! `
回复 sunsong7 的帖子
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问狼兄：

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老狼对万能干细胞的理解是“一人之下，万人之上”，仅次于能够发育成完整生命个体的全能性干细胞；
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每个人的摸样、体型、性格各不相同，成体细胞有二百多种，每种细胞有百种形态和状态不足为怪，乘以细胞种类，那么体细胞也不乏“万种风情”啊（玩笑话）；3 I6 b; N/ S4 J. `/ e# y& {  ~1 T5 E' d% B

$ S' `: g8 y  X" L* l至于畸胎瘤胚胎残留起源成因也只是一种假说，万能细胞（如muse）具有更强的可诱导性，体内可发生细胞重编程，而iPS可以形成畸胎瘤和肿瘤，因此畸胎瘤的“内源性iPS”成因至少通路上是存在的；

marrowstem

问一下：是否已有明确的实验证据支持体内可以发生细胞重编程的过程——诱导逆分化。还是只是一个想法而已！

sunsong7

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) g5 }0 ^% W3 R/ E! w& o  x4 ]虽然还没有内源性iPS的直接报道，但是体内确实可以实现细胞重编程，相关报道：& n% Y9 U- n1 |' s2 L
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Direct in vivo cellular reprogramming involves transition through discrete, non-pluripotent steps 2 ~; d  \+ n: i# N
Jai Prakash Richard, Steven Zuryn, Nadine Fischer, Valeria Pavet, Nadège Vaucamps and Sophie Jarriault* - y8 Q% E* Q9 T: U' f6 e& x* L
*Author for correspondence: sophie@igbmc.fr ( v0 v7 [4 y, E
DEVELOPMENT AND STEM CELLS   Accepted January 31, 2011." I& @4 B6 j& r
18th International C. elegans Meeting( L7 ]8 j0 r- m* [) ^4 N' M

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6 Z: m; N% t! l0 zIn vivo reprogramming of adult pancreatic exocrine cells to bata-cells % G# q6 U* X5 p! T
Qiao Zhou1, Juliana Brown2, Andrew Kanarek1, Jayaraj Rajagopal1 & Douglas A. Melton19 \! V: n% |" j5 `' h
Nature 455, 627-632 (2 October 2008) | doi:10.1038/nature07314; Received 26 June 2008; Accepted 6 August 2008; Published online 27 August 2008
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Department of Stem Cell and Regenerative Biology, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA . n9 g2 c8 I. G% J/ x4 O
Department of Pathology, Children's Hospital, Boston, Harvard Medical School, Harvard Stem Cell Institute, 300 Longwood Avenue, Boston, Massachusetts 02115-5724, USA . k1 \$ T: T. B$ F3 O" x* _% w# z
Correspondence to: Douglas A. Melton1 Correspondence and requests for materials should be addressed to D.A.M. (Email: dmelton@harvard.edu).* k( t2 Y4 V1 V

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2 }+ |% I: W; U5 k4 G+ [Top of pageAbstractOne goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble -cells. The induced -cells are indistinguishable from endogenous islet -cells in size, shape and ultrastructure. They express genes essential for -cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.6 t  Y$ C) O# D* `
http://www.nature.com/nature/jou ... bs/nature07314.html
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Methods Mol Biol. 2010;629:307-21.# U4 w5 }' a' B' g
In vivo reprogramming of human telomerase reverse transcriptase (hTERT) by trans-splicing ribozyme to target tumor cells.
/ ^) J3 p. D0 ?- }& k- dLee SJ, Lee SW, Jeong JS, Kim IH.
* b7 A5 V$ I$ SSourceGenitourinary Cancer Branch, Research Institute, National Cancer Center, Goyang, Korea.
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% s: c& t2 v' E+ e3 QAbstract
: w; X# O! j4 `+ D  XOur understanding of RNA has evolved over the last 20 years from the initial concept that RNA is simply an intermediate in protein synthesis or a structural component maintaining and expressing genetic information. Subsequently, the non-coding RNAs have attracted huge interest and have been developed as therapeutic reagents as well as research tools. An example of RNA-based therapeutic application is the Tetrahymena group I intron-based trans-splicing ribozyme, which cleaves target RNA and trans-ligates an exon tagged at its 3' end onto the downstream U nucleotide of the targeted RNA. Here, we describe the specific trans-splicing ribozyme that can sense and reprogram human telomerase reverse transcriptase (hTERT)-encoding RNA. This ribozyme converts hTERT RNA to therapeutic transgene herpes simplex virus (HSV) thymidine kinase (tk) and exhibits cytotoxicity to various hTERT-expressing cancer cells. For use in cancer therapy, CMV promoter-driven hTERTRibozyme.HSVtk expression cassette is inserted into adenovirus genome and delivered into either subcutaneous or intraspleenic liver-metastasized xenograft. We present here an evaluation of the inhibitory effects of CMV.hTERTRibozyme.HSVtk on tumor growth.
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PMID: 20387158 [PubMed - indexed for MEDLINE]
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$ g/ _& E, q) C* P7 }( l  h8 Hhttp://www.ncbi.nlm.nih.gov/pubmed/203871588 Y! x5 U* E* m2 g7 N
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In vivo reprogramming of hTERT by trans-splicing ribozyme to target tumor cells.
: C+ Z- Z9 I  r1 oby Seung-Hee Hong, Jin-Sook Jeong, Yoon-Jong Lee, Haeng-Im Jung, Kyoung-Sook Cho, … Chang-Min Kim, Byung-Su Kwon, Bruce A Sullenger, Seong-Wook Lee, In-Hoo Kim show all authors 2 c2 c* {0 ]% b% L4 ?8 Q
Molecular therapy the journal of the American Society of Gene Therapy (2008) 2 X- R' V$ f8 \  d5 V
Volume: 16, Issue: 1, Pages: 74-80
6 R! m# w$ {2 P4 ?! l- J8 Q, ?PubMed: 17700543 ! ]+ f) b8 X. _+ D' b' ?
Available from www.ncbi.nlm.nih.gov 9 w8 E1 y' B. g- c/ I2 a1 {

) f* t" w- ^, r6 E; aAbstract  c- F; y+ X/ `( B- c
We have developed and validated a new tumor-targeting gene therapy strategy based upon the targeting and replacement of human telomerase reverse transcriptase (hTERT) RNA, using a trans-splicing ribozyme. By constructing novel adenoviral vectors harboring the hTERT-targeting trans-splicing ribozymes with the downstream reporter gene (Ad-Ribo-LacZ) or suicide gene (Ad-Ribo-HSVtk) driven by the cytomegalovirus (CMV) promoter, we demonstrated that this viral system selectively marks tumor cells expressing hTERT or sensitizes tumor cells to prodrug treatments. We confirmed that Ad-Ribo-LacZ successfully and selectively delivered a ribozyme that performed a highly specific trans-splicing reaction into hTERT-expressing cancer cells, both in vitro and in a peritoneal carcinomatosis nude mouse model. We also determined that the hTERT-specific expression of the suicide gene in the Ad-Ribo-HSVtk, and treatment with the corresponding prodrug, reduced tumor progression with almost the same efficacy as the strong constitutive CMV promoter-driven adenovirus, both in cancer cell lines and in nude mouse HT-29 xenografts. These observations provide the basis for a novel approach to cancer gene therapy, and demonstrate that trans-splicing ribozymes can be employed as targeting anti-cancer agents which recognize cancer-specific transcripts and reprogram them, thereby combating cancerous cells.1 n4 N% Q: Y) E; k5 ?* l

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marrowstem

Ok，如果是这样，那你怎么知道体外诱导出来的iPS细胞是体内原本就存在的iPS细胞，还是体细胞被重编程诱导了。

sunsong7

呵呵，这个我就不知道了，需要请教山中伸弥教父