@@肿瘤干细胞文献阅读活动@@——第一期

饶冠华

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第一期活动就讨论一下最近发表的关于肿瘤干细胞分化生成肿瘤血管的文章吧。详情如下：3 c7 s+ c' e, }* Z3 _
1. Nature. 2010 Dec 9;468(7325):829-33. Epub 2010 Nov 21.6 x  ?3 k! N3 ]. L

" r- Q& @6 k" K( T* q4 @Glioblastoma stem-like cells give rise to tumour endothelium.# v; o* R! s% W( k/ {0 n7 r
Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V.
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Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.& ^' R* L0 G* `5 W. t+ T1 g0 W
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Comment in:
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0 Z& Y' K6 g& g& ?9 m3 a1 ~1 S& H! yNature. 2010 Dec 9;468(7325):770-1. 1 G6 x9 w& ?* v
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Abstract
0 C. L- e# l8 B/ e2 k  a0 {Glioblastoma (GBM) is among the most aggressive of human cancers. A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia. Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poorly defined. Here we demonstrate that a subpopulation of endothelial cells within glioblastomas harbour the same somatic mutations identified within tumour cells, such as amplification of EGFR and chromosome 7. We additionally demonstrate that the stem-cell-like CD133(+) fraction includes a subset of vascular endothelial-cadherin (CD144)-expressing cells that show characteristics of endothelial progenitors capable of maturation into endothelial cells. Extensive in vitro and in vivo lineage analyses, including single cell clonal studies, further show that a subpopulation of the CD133(+) stem-like cell fraction is multipotent and capable of differentiation along tumour and endothelial lineages, possibly via an intermediate CD133(+)/CD144(+) progenitor cell. The findings are supported by genetic studies of specific exons selected from The Cancer Genome Atlas, quantitative FISH and comparative genomic hybridization data that demonstrate identical genomic profiles in the CD133(+) tumour cells, their endothelial progenitor derivatives and mature endothelium. Exposure to the clinical anti-angiogenesis agent bevacizumab or to a γ-secretase inhibitor as well as knockdown shRNA studies demonstrate that blocking VEGF or silencing VEGFR2 inhibits the maturation of tumour endothelial progenitors into endothelium but not the differentiation of CD133(+) cells into endothelial progenitors, whereas γ-secretase inhibition or NOTCH1 silencing blocks the transition into endothelial progenitors. These data may provide new perspectives on the mechanisms of failure of anti-angiogenesis inhibitors currently in use. The lineage plasticity and capacity to generate tumour vasculature of the putative cancer stem cells within glioblastoma are novel findings that provide new insight into the biology of gliomas and the definition of cancer stemness, as well as the mechanisms of tumour neo-angiogenesis.: B* e+ G6 D4 s

8 _0 \2 n5 A) T) X5 JPMID: 21102433 [PubMed - in process]/ S- D" {7 E! w( a
全文：
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# t6 N8 }  b; n" ?4 [2.Nature. 2010 Dec 9;468(7325):824-8. Epub 2010 Nov 21.
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/ _; A7 W- x: U# d. vTumour vascularization via endothelial differentiation of glioblastoma stem-like cells.
$ m: R* d3 R. _' o  hRicci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R.7 A( G# m) L' a5 R. x- x1 I7 }

' ?) L( C4 k+ x$ h5 W# n( Q1 kDepartment of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
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( L$ M7 Y/ X, RComment in:; O9 P; h, C1 B8 O9 ]- W0 b0 ?; m
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Nature. 2010 Dec 9;468(7325):770-1.
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$ H6 I0 k8 ^8 P* cAbstract
4 w7 W/ H* r5 h- o: aGlioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.! x% x) t& j4 h% b8 L- z4 z

& i" E( i2 y1 f" F3 ?1 i9 t* ?6 qPMID: 21102434 [PubMed - in process]. f% G2 a0 P1 \; e2 \, Q+ ^9 p
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3. 同期评论：
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  m/ w0 v0 i- Q2 o- W可以从以下几个方面发表见解：) y% g7 r. L% i
1. 本文研究的背景是什么？此实验室在本领域发表过什么其他文章？
# }0 k7 r$ @% w4 x4 @! c4 v# s8 e% u! Z2. 文章的立意是否新颖，有没有创新的内容在里面？闪光点在哪里？# i: v) q1 r- _* @
3. 本文对了解肿瘤，促进肿瘤研究有何意义？
. N) l1 l9 B/ b( k: ~4. 实验方法思路有没有我们可以借鉴的？
/ `! \9 E- }  C9 I* M) W+ t5. 本文有没有什么实验漏洞？或者说我们有没有替代的方法或者更好的方法去论证本文想阐述的问题？6 }2 k/ b% @1 K& \! A: M& G
6. 本文章有没有继续往下进行的可能性？如果有，后续的课题应该从哪些方面着手？
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饶冠华

不知道大家文献都看得怎么样了？我最近一段时间比较忙，文章虽然很早就打印出来放在电脑旁边了，但一直没抽出时间去仔细阅读。由于没有很完整的时间去系统读这两篇文献，我就一边阅读一边和大家讨论吧。如果疏忽和错误的地方，还请大家指正。我们的口号就是：一起交流，一起进步！

饶冠华

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回复 饶冠华 的帖子
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' H0 \2 n: X! e, T$ k+ {. f首先看看两篇文章的标题：
5 e! J& y- r7 M# S2 A4 H1.tumor vasularization via endothelial differentiation of glioblastoma stem-like cells.$ e8 z! `0 p! ~
2.Glioblastoma stem -like cells give rise to tumor endothelium.
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6 ]; j' x% r2 w$ J拿到这篇文章之后，我们会注意到的第一个问题是：两篇文章都是以glioblastoma为研究对象的，那么针对其他实体瘤呢？有没有类似的想象？- M) U2 a/ _  f& b9 n
接着往下分析，第一个标题和第二个标题都提到肿瘤血管内皮可以由干细胞样的胶质瘤细胞分化而来，那么就会接着想到，既然这部分血管内皮细胞来源于肿瘤细胞，那么也肯定会带上肿瘤细胞的印记,比如： 1.肿瘤细胞很多都是染色体紊乱，具有异倍体的特征，那么这部分内皮细胞也应该会呈现染色体紊乱。2. 如果我们利用某种技术标记上肿瘤干细胞，那么体内动物实验应该能找到部分细胞同时表达血管内皮Marker和之前我们给肿瘤干细胞做的标记。3. 如果肿瘤血管内皮细胞会来源于肿瘤干细胞，那么占有比例会有多少呢？什么情况下会由正常内皮祖细胞分化成肿瘤血管，什么情况下会需要肿瘤干细胞来参与呢？这个过程是通过什么来调控的？4. 从肿瘤干细胞分化而来的内皮细胞形成的血管会与正常内皮细胞形成的血管有什么不一样的地方么？功能或者形态方面？5. 除了内皮细胞之外，肿瘤干细胞还能分化成其他类型的细胞么？比如成纤维细胞？或者其它？
; M0 K' U2 {# t, Y（从标题来看，目前我只能提出这么些问题，欢迎大家补充）

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接着往下看通讯作者，分别来自意大利的Ruggero De Maria和美国纽约Memorial Sloan Kettering Cancer Center 的 Viviane Tabar，有兴趣的同学可以Google一下这两个实验室以前分别做什么方向？

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回复 深海寂寞鱼 的帖子7 u4 m' g, m" W& N! a/ ?5 J

! f* ?6 n' m4 O; O8 Q+ I, K晚上有人请吃饭，回来再看你的报道哈~~今天晚上吃完饭我也好好看看这两篇文献~~

饶冠华

回复 深海寂寞鱼 的帖子
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& ^3 t# a( h2 I- ^4 ?咦 突然发现 如果你有anti-human的抗体 为什么当时不先染一下呢？ 如果anti-human的抗体能染上的话 那至少能说明有从肿瘤细胞分化而来的血管内皮细胞呀...

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呵呵 我没法发邀请~~ 只能他们自己申请加入~~ 不过直接回帖也可以的