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Whitehead研究所研究人员在乳腺组织发现一种分化的细胞，可自发转化成类似于干细胞的状态，这是第一次在哺乳动物细胞中观察到。这些结果反驳了科学教条主义—认为分化是一种单项路径，一旦细胞分化，他们不能依靠自己回到干细胞状态。
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5 X9 R4 O4 \& T. B该惊人的发现发表在PNAS上，可对癌症治疗的进展，尤其是根除癌症干细胞具有重要意义。9 [* }. W& J* ^7 N6 ^5 R
* }0 S" i- j. ]) AWhitehead研究所的Robert Weinberg说，如果通过某个特定的介质消除肿瘤内的癌症干细胞，一些尚存的非干肿瘤细胞（non-stem tumor cell）将通过自主去分化（de-differentiation）的过程产生新的癌症干细胞。癌症干细胞是唯一能够对体内的肿瘤进行再播种的细胞。% J E- s# Q4 b: u
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在分化过程中，未完全分化的干细胞可培育成许多具有特定功能的不同细胞类型。这些分化的细胞可共同作用形成组织和器官。在乳腺组织中，分化的基底细胞和管腔细胞结合形成乳管。
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该论文的第一作者，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。5 Y7 E6 |% c; X
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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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- f! i7 r8 a+ x/ I/ g9 f直到现在，没有人表明分化的哺乳动物细胞，像这些基底细胞，能够自发地恢复到干细胞状态。观察基底细胞是否会变成癌症干细胞，Chaffer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。
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: V$ l) V9 y) I' ]) E( k% L目前，对于癌症治疗的研究着重于消除癌症干细胞，Weinberg警告说这些基底细胞的可塑性表明了一种更加复杂的状况。
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未来针对癌症的药物治疗必须根除其癌症干细胞，以及消除肿瘤中的非干细胞（non-stem cell），这两个群体都必须根除。1 J2 S4 V3 g k4 i1 ]6 m2 I
0 J# N; Q0 w: I' Z: S$ ?* _Chaffer正着重于研究究竟是什么推动这些灵活的细胞进行去分化，并且针对癌症细胞，如何阻止细胞转化成癌症干细胞。% @+ H: [3 _; d6 A
2 e- c8 z4 |5 d3 W- @这种可塑性能够自然发生，似乎该推动剂可能是转化为干细胞的生理机制。我们相信某种细胞对于这种推动剂更加敏感，并且该过程在癌症细胞中发生地更加频繁。$ {, `- s8 Y0 U1 P8 a
（生物谷Bioon.com）
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Scientists Identify a Surprising New Source of Cancer Stem Cells
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ScienceDaily (Apr. 11, 2011) — Whitehead Institute researchers have discovered that a differentiated cell type found in breast tissue can spontaneously convert to a stem-cell-like state, the first time such behavior has been observed in mammalian cells. These results refute scientific dogma, which states that differentiation is a one-way path; once cells specialize, they cannot return to the flexible stem-cell state on their own.
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This surprising finding, published online in the Proceedings of the National Academy of Sciences (PNAS), may have implications for the development of cancer therapeutics, particularly those aimed at eradicating cancer stem cells.
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+ Q4 a$ N/ G% N. o. t"It may be that if one eliminates the cancer stem cells within a tumor through some targeted agent, some of the surviving non-stem tumor cells will generate new cancer stem cells through spontaneous de-differentiation," says Whitehead Founding Member Robert Weinberg. Cancer stem cells are uniquely capable of reseeding tumors at both primary and distant sites in the body.
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During differentiation, less-specialized stem cells mature into many different cell types with defined functions. These differentiated cells work together to form tissues and organs. In breast tissue, for example, differentiated basal cells and luminal cells combine to form milk ducts.
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While analyzing cells from human breast tissue, Christine Chaffer, who is a postdoctoral researcher in the Weinberg lab and first author of the PNAS paper, observed a small number of living basal cells floating freely in the tissue culture medium.
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# W" H5 M/ b8 g7 U2 d% uIntrigued by the cells' unusual behavior, Chaffer conducted further targeted investigations, including injection of the floating basal cells into mice. After 12 weeks she found that the injected basal cells gave rise to milk duct-like structures containing both basal and luminal cells -- a clear indication that the floating cells had de-differentiated into stem-like cells.+ [6 [" [6 [5 K4 d( C0 T
& a) `. ^) q5 S8 W6 KUntil now, no one has shown that differentiated mammalian cells, like these basal cells, have the ability to spontaneously revert to the stem-like state (a behavior described as plasticity).
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1 N$ C2 B4 Y: t0 l3 q0 i; i% iTo see if basal cells could become cancer stem cells, Chaffer inserted cancer-causing genes into the cells. When these transformed cells were injected into mice, the resulting tumors were found to include a cancer stem cell population that descended from the original injected basal (more differentiated) cells. These results indicate that basal cells in breast cancer tumors can serve as a previously unidentified source of cancer stem cells.+ X6 Z; ]3 U* b
: ^' O. e, Q' F; QAs research for new cancer therapies has recently focused on eliminating cancer stem cells, Weinberg cautions that the plasticity seen in these basal cells suggests a more complicated scenario than previously thought.
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"Future drug therapies that are targeted against cancer will need to eliminate the cancer stem cells and, in addition, get rid of the non-stem cells in tumors -- both populations must be removed," says Weinberg, who is also a professor of biology at MIT. "Knocking out one or the other is unlikely to suffice to generate a durable clinical response."
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& z9 `1 X! ?2 z0 v/ jChaffer is now focusing on what actually prompts these flexible cells to de-differentiate, and in the case of cancer cells, how to stop the cells from converting into cancer stem cells.2 h5 O! _# o. ?0 @1 x
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"This plasticity can occur naturally, and it seems that the trigger may be a physiological mechanism for restoring a pool of stem cells," says Chaffer. "We believe that certain cells are more susceptible to such a trigger and therefore to conversion from a differentiated to a stem-like state, and that this process occurs more frequently in cancerous cells.") y* d& m$ y; E1 r
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In the case of normal epithelial cells, the observed behavior may also allow patient specific adult stem cells to be derived without genetic manipulation, holding promise for degenerative disease therapy.
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This research was supported by the National Health and Medical Research Council of Australia, National Institutes of Health (NIH), Massachusetts Institute of Technology's Ludwig Center for Molecular Oncology, the Breast Cancer Research Foundation, and a Department of Defense (DoD) Breast Cancer Research Program (BCRP) Idea Award.
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8 |( Z' b6 m; e* E* b* B5 SJournal Reference:
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1.Christine L. Chaffer, Ines Brueckmann, Christina Scheel, Alicia J. Kaestli, Paul A. Wiggins, Leonardo O. Rodrigues, Mary Brooks, Ferenc Reinhardt, Ying Su, Kornelia Polyak, Lisa M. Arendt, Charlotte Kuperwasserd, Brian Bierie, Robert A. Weinberg. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proceedings of the National Academy of Sciences, 2011
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发表于 2011-4-15 08:47
发表于 2011-4-28 15:31
