! p; w: a O* \; k5 p8 C0 A全文如下: ) Q* Z' S. i) AScientists probe limits of 'cancer stem-cell model'; Melanoma does not fit the model" g, ?& k- V1 v4 i$ R% \& s8 ]
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2 I Y9 |" F+ ^ G $ J# L* g$ l, N( m6 J; L HA melanoma skin lesion on the chest of a 45-year-old male patient. The lesion measures 1.2 inches by 1.6 inches. Photo courtesy of Dr. Timothy Johnson. 9 m7 s) y9 ]( `9 u4 E' Y: f+ \. ]& V+ ?9 `& ], o0 D! y# S
(PhysOrg.com) -- One of the most promising new ideas about the causes of cancer, known as the cancer stem-cell model, must be reassessed because it is based largely on evidence from a laboratory test that is surprisingly flawed when applied to some cancers, University of Michigan researchers have concluded. 1 o+ E3 x1 [: ~/ i 9 s @5 ~+ _/ G. LBy upgrading the lab test, the U-M scientists showed that melanoma—the deadliest form of skin cancer—does not follow the conventional cancer stem-cell model, as prior reports had suggested. ( Z' _, [4 v7 j: J# x8 R+ e J! p- d6 |4 Y' W. v- w# l
The findings, to be published as the cover article in the Dec. 4 edition of Nature, also raise questions about the model's application to other cancers, said Sean Morrison, director of the Center for Stem Cell Biology at the U-M Life Sciences Institute. + O* l# B$ s, R& t- N$ c* ~7 |
"I think the cancer stem-cell model will, in the end, hold up for some cancers," Morrison said. "But other cancers, like melanoma, probably won't follow a cancer stem-cell model at all. The field will have to be reassessed after more time is spent to optimize the methods used to detect cancer stem cells.", W. d7 g2 _& A- z
4 U! K+ [7 I- v1 S0 S9 QThe cancer stem-cell model has steadily gained supporters over the last decade. It states that a handful of rogue stem cells drive the formation and growth of malignant tumors in many cancers. Proponents of the controversial idea have been pursuing new treatments that target these rare stem cells, instead of trying to kill every cancer cell in a patient's body./ a( i; h+ J- g) n
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But in a series of experiments involving human melanoma cells transplanted into mice, Morrison's team found that the tumor-forming cells aren't rare at all. They're quite common, in fact, but standard laboratory tests failed to detect most of them. ' [6 W C( `+ f7 F3 i3 z5 V) O6 V. T c" A. l
Scientists previously estimated that only one in 1 million melanoma cells has the ability to run wild, exhibiting the kind of unchecked proliferation that leads to new tumors. These aggressive interlopers are the cancer stem cells, according to backers of the model. 5 A. a" f ~6 a* }; R6 _) D) ]. |, D6 G5 N7 z. g4 t
But after updating and improving the laboratory tests used to detect these aberrant cells, Morrison's team determined that at least one-quarter of melanoma cells are "tumorigenic," meaning they have the ability to form new tumors. The laboratory tests are known as assays.0 U4 u2 L; O% K9 s6 D) t2 g
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"The assay on which the field is based misses most of the cancer cells that can proliferate to form tumors," Morrison said. "Our data suggest that it's not going to be possible to cure melanoma by targeting a small sub-population of cells." m6 u; p2 M& C % s+ K( ?( o# |4 o( N( E8 |) hMelanoma kills more than 8,000 Americans each year. The human melanoma cells used in the mouse experiments were provided—with the patients' consent—by a team from the U-M's Multidisciplinary Melanoma Program, one of the country's largest melanoma programs and part of the U-M Comprehensive Cancer Center.' q2 q6 l9 ^' ]5 X4 X
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"People were looking to the cancer stem-cell model as an exciting new source for the development of life-saving cures for advanced melanoma," said Dr. Timothy Johnson, director of the U-M melanoma program and a co-author of the Nature paper. "Unfortunately, our results show that melanoma does not strictly follow this model.9 D. n0 f+ i6 X, B
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"So we'll need to redirect our scientific efforts and remain focused on the fundamental biological processes underlying the growth of melanomas in humans," said Johnson, a cutaneous oncologist. "And as we pursue new treatments for advanced melanoma, we'll have to consider that a high proportion of cancer cells may need to be killed.", D! t* a. {0 p, ^/ ]
# u" _- I. w' o% V( S* NMorrison and Johnson stressed that the team's findings do not broadly invalidate the cancer stem-cell model. Cancer stem cells likely do exist in some forms of cancer but are "probably much more common than people have been estimating," Morrison said. . B$ Y* K& Y. X w' t4 X1 { , X- |! o' T7 C# {2 m1 |The standard technique used to detect tumor-causing cancer cells in mouse transplants is called the NOD/SCID assay. NOD/SCID mice have defective immune systems. Scientists use the severely immunocompromised mice because they don't reject transplanted human cancer cells the way normal mice would. 9 e5 ]/ ]9 o! J; w ^" {/ `0 A 2 j1 j3 r4 C! EHowever, while the immune system in NOD/SCID mice is impaired, it's not completely inoperative. The mice lack T and B immune cells but still possess natural killer cells, which attack and destroy many of the transplanted human cancer cells. 2 {4 g ]/ S; j8 P( P" q3 T( s4 P
Morrison's team replaced NOD/SCID mice with mice that lacked T cells, B cells and natural killer cells—and made a few other improvements to the assay. Using the modified assay, they found that about one in four transplanted melanoma cells formed tumors in the mice.! A# U; e& ?+ W3 n, z; h5 ]
" u% a3 I( p9 t2 e4 F9 zThey concluded that previous studies using NOD/SCID mice vastly underestimated the number of tumor-causing melanoma cells, partly because natural killer cells wiped out many of the cancer cells. But once the natural killer cells were eliminated, the "more permissive conditions" allowed many of the transplanted melanoma cells to survive and thrive, the authors wrote.! A n8 i! F) |0 u
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Co-lead authors of the Nature paper are Life Sciences Institute research fellows Elsa Quintana and Mark Shackleton. In addition to Morrison and Johnson, other co-authors are U-M surgical oncologist Dr. Michael Sabel and U-M dermatopathologist Dr. Douglas Fullen. * @+ ]3 {! v! t8 q* X/ f ! H! p4 S- Q- U! fProvided by University of Michigan 作者: oldmac7 时间: 2010-3-29 15:50
9 ~9 v7 N; L7 C$ Q另一篇能够支持cancer stem cell hypothesis 的:6 }. i. ~7 e( Q$ T u
8 E C6 K: P" sCommon Trigger In Cancer And Normal Stem Cell Reproduction Discovered By Stanford Scientists + B+ c4 u2 G, ^3 c- PMain Category: Breast Cancer! Y, o, a" V4 a
Also Included In: Cancer / Oncology; Stem Cell Research/ L+ s8 V8 [( [ \5 o+ h
Article Date: 08 Aug 2009 - 0:00 PDT- z9 E# M+ V: h4 w
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Researchers at Stanford University School of Medicine have discovered, for the first time, a common molecular pathway that is used by both normal stem cells and cancer stem cells when they reproduce themselves. : B5 q" l# v$ y$ a- m5 p
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In a paper published Aug. 7 in the journal Cell, Michael Clarke, MD, the Karel H. and Avice N. Beekhuis Professor in Cancer Biology, and his colleagues showed that breast cancer stem cells and normal breast stem cells turn down the creation of a specific group of cell signals when they are reproducing. Increasing the amount of one of these signals, called miR-200c, strongly suppressed the ability of both cancer stem cells and normal stem cells to divide and reproduce. 4 Y9 \4 d1 b: E# U; r
! t% J+ m. m, MThe discovery of a common regulatory pathway in both kinds of stem cells supports the idea that cancer stem cells and normal stem cells share fundamental properties. "This very strongly supports the cancer stem cell hypothesis," said Clarke, who is associate director of the Stanford Stem Cell Biology and Regenerative Medicine Institute and a member of the Stanford Cancer Center. "A lot of people have speculated that there was this molecular link between these two kinds of cells (cancer stem cells and normal stem cells), but this is the first time we have actually identified it." 1 m# Y) a2 c) O" x ` u 1 r5 _) i j% U+ SThe cancer stem cell hypothesis states that cancers are a collection of many different kinds of cells, only a very few of which create and sustain the cancer. These are the cancer stem cells, which share many traits with normal stem cells. ' M' l% v" A, b; _" S2 }( B. v" M3 w+ H; i2 R
While most cells in the body cannot reproduce themselves, stem cells have the ability to do so, and can also create the cells that mature into various tissues. Blood stem cells, for instance, which reside in the bone marrow, have the ability to create new blood stem cells and also to create all the different types of mature blood cells. - V& K& p7 C+ y9 O% K
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While the current discovery is important evidence of how cancer stem cells operate, it does not automatically lead to new cancer therapies. "The problem is that if we attack cancer using this mechanism, it is also going to affect normal stem cells which are essential for our survival," Clarke said. But understanding how cancer cells sustain themselves may in the future offer new ways of attacking the disease. "The hope is that we can find nuances that distinguish between how normal stem cells renew themselves and how cancer stem cells do so, and then use those differences to attack only the cancer," said Clarke. , E1 S! I8 m+ i) a% K$ V. z! q1 H4 @: p2 m# z1 f
The research also demonstrates the power of conducting studies that zero in on cancer stem cells rather than screen all cancer tumor cells. In the past, for instance, scientists tried to gain insight into how cancer cells reproduce by looking at molecular signals in all the cancer cells in a tumor. But this molecular detective work did not reveal cancer stem cells' use of the miR-200c pathway, probably because signals from cancer stem cells were lost in a crowd of molecular signals from the far more numerous non-stem cells. & ^, m( E' k7 w+ F9 n
% t# y* D$ [7 f. y) {' x5 @Clarke and his colleagues therefore isolated the cancer stem cells first and then did the analysis. Clarke noted that it is technically challenging to isolate cancer stem cells, which can be outnumbered by generic tumor cells 100 to 1, but the rewards can be dramatic. ; I; f, F0 |# N8 m) {2 M ! I# |! ^) Y( eBy analyzing only stem cells, the link between the molecular signals that control reproduction in cancer stem cells and normal stem cells became apparent. ' `# o- n$ x0 V% h$ f9 k) A $ w+ s7 G$ f" t4 g4 ~6 U"If you are looking at all the cells in a tumor, it's like looking for a crying child lost in an auditorium of cheering people," Clarke said. "You can't hear the child crying until you remove everyone else from the auditorium, and then the sound will pop out." $ t6 G$ D) Q! q3 F0 a
) Q- j* X; H1 U$ ^* WNotes: 3 S8 s5 J% q& t9 cOther Stanford researchers involved in the project were Yohei Shimono, PhD; Maider Zabala, PhD; Robert Cho, MD; Neethan Lobo, PhD; Piero Dalerba, PhD; Dalong Qian, PhD; Acting Assistant Professor of Radiation Oncology Maximilian Diehn, MD, PhD; Huiping Liu, PhD; Sarita Panula, PhD; Eric Chiao, PhD; and Professor of Obstetrics & Gynecology Renee Reijo-Pera, PhD. ( B4 N3 I+ ~" F. d2 a6 f
The research was supported by the California Breast Cancer Research Program of the University of California, the Fundacion Alfonso Martin Escudero, the Fulbright Foundation, the National Institutes of Health, the Breast Cancer Research Foundation, the Morton Family Foundation and the Ludwig Foundation. ) B3 J- C2 g9 s; }; A [; ?; b7 J# v5 V
. Z2 c0 D2 X3 ?% Q6 wSource: & Y0 i* ]. ~ u0 g8 WChristopher Vaughan R7 u! |3 g- j5 O1 [; W: w
Stanford University Medical Center 作者: oldmac7 时间: 2010-3-29 17:15
不过, 癌症干细胞理论，可能只适用于某些癌症和某些病人，所以, 学习癌症干细胞模型也是必要的.) k" k- W$ o1 ?0 g# ?) G8 i" s
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* c8 C' j+ t+ M4 o( D1 DDissecting Cancer Stem Cell Theories 剖析肿瘤干细胞理论9 @- S9 C( Q2 G9 W. S$ i1 V$ m: g `* f
Whether Model Is Apt Seems to Depend on Type of Cancer and Individual Patient ' Z4 f2 S* P! o. i( o% K& r: u8 |1 U: n3 W% j w% c* G1 D
Feb 1 2010 Gail Dutton + P$ [7 B6 L+ A9 S% u6 } 9 Z) D) C% @" J2 `5 J$ z7 k1 X1 ~% o2 D9 G
Pigmentation due to melanin deposition in a section of a melanoma stained with hematoxylin and eosin (University of Michigan Center for Stem Cell Biologics)" ~) K7 a8 Y8 N% z1 ]1 f G. _
5 ^3 H2 M$ {5 M* v, UThe cancer stem cell theory, which holds that a small number of tumorigenic cells are responsible for metastases, applies only to some cancers and possibly to certain patients, according to Sean Morrison, founder of OncoMed, now at the University of Michigan Center for Stem Cell Biologics. Therefore, learning when the cancer stem cell model is valid is a vital step to understanding and, ultimately, treating cancer. $ d* W2 T8 ~5 G5 N( \& u* Z. C: ^ 2 s1 F1 d; [9 L. E7 ?' _“Not every cancer cell is bad. Some cancer cells differentiate into cells that are benign,” Dr. Morrison emphasized as he opened the cancer stem cell workshop at the American Society for Cell Biology (ASCB) meeting in San Diego in December. “Cancer stem cells have the unique capability of proliferating.”3 g: _- p6 Z' t2 u
, m, [) g8 N. u2 |& ~The stochastic, or clonal evolution, model dictates that, “despite the heterogeneity (in cancer), cells of many different phenotypes are capable of proliferating extensively and forming new tumors,” Dr. Morrison summarized. 0 b, x0 r$ c& l4 ^1 j/ }) B# Q/ C9 y # Y: b+ ~5 j2 u/ M( l* DThe cancer stem cell model, in contrast, says that “cancer stem cells are uniquely capable of proliferating extensively and forming new tumors, and that they go through an aberrant process of differentiation giving rise to phenotypically diverse cancer cells with a limited capacity to divide.” Which of these two theories is correct seems to depend upon the type of cancer. * X6 \& z/ Q$ u! C" J4 P# U) F+ n* h; E
Researchers are trying to determine whether such tumorigenic potential is within all cancer cells, or whether it is confined to a small number of cells. “If the cancer stem cells are rare,” he said, “the ability to identify these cells is critical to studying them. If the ability to become tumorigenic is common, distinguishing them is less valuable.”& ~ ]* I: f0 h7 n* f+ }/ l7 p! t
* E, F" j! H( u5 P8 F“Studies are showing that a variety of cancers follow the cancer stem cell model, where markers can be identified that distinguish cancer stem cells from nontumorigenic cancer cells,” Dr. Morrison explained. “One of the untested, but underlying assumptions of the cancer stem cell model is that the difference that distinguishes tumorigenetic and nontumorigenetic cells is epigenetic, rather than genetic in nature.” 3 m0 C+ @ o$ e( |! s% ?" j
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The clonal evolution model predicts genetic changes that will be deleterious to the cell, so the observation that not every cell is tumorigenetic is consistent with the clonal evolution model. What’s different about the cancer stem cell model is the idea that you can have cancer from only a small minority of the cells, that can differentiate into nontumorigenic cells, he said.( M' X# W; T0 m [
( f4 {( H% }% w2 QMost of the talk about cancer stem cells is mainly predictions, he cautioned. Conclusions about the fraction of cancers that follow the stem cell model are based primarily upon markers that distinguish tumorigenetic from nontumorigenetic cells. “So, all of the conclusions depend upon the robustness of these markers,” he noted, at least some of which are less robust than initially believed. Additionally, “Do some patients follow the model and others not? Does metastasis arise exclusively from migration of cancer stem cells? That makes intuitive sense, but isn’t tested.” S" p1 I: Y& M # H7 ~# s0 l T1 a7 h“We can’t make general conclusions that cancer stems cells are less sensitive to therapy,” Dr. Morrison said. There are several potential explanations for drug resistance. For example, “the apparent resistance may reflect a log kill, in which a therapy eradicates 95 percent of the tumorigenic cells but the remaining five percent proliferate.”# ? f0 V. J2 o: i. s. Z
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In his own lab, experiments with acute myeloid leukemia and acute lymphoblastic leukemia in mice showed that not every cell proliferates and transfers disease. “Cells that express a phenotype similar to hematopoietic stem cells are 400-fold enriched for leukemigenic activity as compared to the bulk population of bone marrow cells.” That supports the idea, he said, that “not every cell has the capacity to transmit disease, and cells that transfer disease are rare.” A similar study also showed that chronic myeloid leukemia (CML) followed the cancer stem cell model. , t! ]4 J' q7 ^5 {: o& V5 o8 e5 ]* Z6 A$ p6 U! c2 y& a
In studies of imatinib response against CML using a different mouse model, imatinib shrunk the (enlarged) spleen to normal levels. It did not cure the disease though. In fact, cells from these mice were more capable of transferring disease, showing that the “CML stem cells are orders of magnitude more resistant to imatinib than other cancer cells in the same mice, which is consistent with clinical experience.” * r( ], g- k+ A" t- [& T" {- W( Y4 E, j3 P" ]
Melanoma is another model that was thought to follow a cancer stem cell model. It doesn’t, Dr. Morrison reported, based upon transplanting melanoma cells from several patients into NOD/SCID mice. After eight weeks, only a minority of cells had formed tumors. At 28 weeks, however, the ratio of tumorigenic cells had increased nearly eightfold. “One issue, therefore, is that people sometimes don’t run their assays long enough to detect the full spectrum of tumorigenic cells.” K! S) _6 K' M" D4 R2 t+ D& e / Y7 C' E+ e0 j6 YAssay Optimization' ]; _' a( }% B4 y/ U) N2 {4 c; V
4 \/ a9 V3 q* A/ M) T2 OAs part of this research, Dr. Morrison’s lab decided to optimize the off-the-shelf assay to see whether changes could detect a broader range of cancer cells. “In addition to going longer and detecting a 10-fold increase in tumorigenic cells, if we use more highly immunocompromised mice we get almost a 200-fold increase in the detectable frequency of tumorigenic cells. Co-injection with Matrigel™ (which generally improved cell engraftment and thus increases cell survival without conferring tumorigenicity) yielded up to a 20-fold increase.! I1 m7 |5 j/ g: H
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“Modifications in xenograft assays combine to dramatically increase the detectable frequency of tumorigenic cells, so that they were actually quite common,” Dr. Morrison said. In a larger study, initial data indicated that one in one million cells has the potential to form a tumor but, by slightly modifying the assay, the ratio changed to one in four.6 L$ M1 z p5 m( q+ g
* @9 j$ {7 C. H9 c“Therefore, for the first time in cancer biology, we can study tumorigenesis from single human cancer cells in vivo.” Rather than proving that metastatic melanoma doesn’t follow the cancer stem cell model, it proves that the tumorigenic cells are frequent.# ^6 i3 |6 P4 f9 ~# S
. r; _2 S% t8 b/ @" o. N" c, ]“A separate question is whether the 28 percent of cells in which we can detect tumorigenic capacity are intrinsically different from the nontumorigenic cells that we cannot detect,” Dr. Morrison continued. In his experiments, involving 50 markers, in which 17 that are frequently heterogeneously expressed, the positive and negative fractions resulting in tumorigenesis. “We are unable to detect a hierarchical organization in melanoma, having looked very hard.” If such a marker is eventually found, he suggests it will have a very shallow hierarchy." R! K; X* {4 w
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The second portion of the workshop, led by Franziska Michor, Ph.D., computational biologist at Memorial Sloan-Kettering, addressed therapeutic resistance and the origin of cancer stem cells. , q& y/ j* l1 @/ v( D \; `' Z) p) _* j0 f6 ]0 ] e1 h
“If you have a drug that kills tumor stem cells, then over time, the tumor stem cell population will die out. If you have drugs that kill tumor cells but leave the cancer stem cells intact, then the tumor cell population will grow back,” she hypothesized.; r2 a# s0 B; p1 x U
7 r9 g, q/ s" F" f; o0 Y0 YIn investigating the molecular response to imatinib among 68 patients, Dr. Michor found two distinct response slopes—one at 20 days life span and another at 125 days life span during therapy—with two distinct decay rates. The main body of cancer cells was depleted at a rate of 5% per day, while the other cells were depleted by 0.8% per day. This dramatic difference indicates that there are distinct subpopulations of cancer cells. - u8 y( q) n8 Z) s! ?9 ~# ^
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The idea that distinct subpopulations of cancer cells exists is further supported by a German study of patients who discontinued imatinib therapy after three years. Within one week, the cancer cells rapidly rebounded in 60% of the patients, peaking at levels higher than baseline. Therefore, it appears that cancer stem cells were not depleted by the drug and are, in fact, driving the disease. “There’s something going on that leads to resistance to imatinib,” Dr. Michor said. 3 u& L+ G' K' t$ @ 6 z% D- L' R% m6 ^" X3 H- jBecause imatinib is so specific as to be useless if a single base changes, it may be possible to answer that question while exploring the origin of tumorigenic cells. To do so, she turned to a mathematical analysis of the evolution of cancer stem cells, focusing upon identifying the mutation that triggered their drug resistance and considered several theories: that tissue-specific stem cells accumulated all the mutations needed to transform into tumor cells, that progenitors also accumulated the necessary mutations, and that the mutation conferring self-renewal to progenitors first arises in the stem cells without changing their phenotype. 3 n, {$ c8 o* r9 ~. [6 J, @! [. M. N% ^' L/ K
Based upon her work with JAK2V617F mutations, she determined that progenitor cells are the most likely cell of origin for those mutations, which lead to cancer. This finding also may be relevant to other tumor types in tissues organized with a differentiation hierarchy.+ d7 _7 L& H; _6 D F
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Her next step was to identify the predicted first mutation. Using primary glioblastomas, Dr. Michor investigated cells in the subventricular zone of the brain that targets for transfection. Using mathematical modeling of a small number of cell divisions, she found that, “self-renewing transit amplifying cells are the most likely cell of origin for gliomas.”. B3 h j) a- N, {
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In general discussions, Dr. Michor broached the idea that “some cancers really seem to follow the cancer stem cell model but are reversibly organized.” The role of microenvironments also was touched upon and should be the subject of additional research. “Tumor microenvironments are very important, but we don’t know how,” Dr. Morrison said. Microenvironments appear to kick off morphogenetic processes, so the markers that often are used become moving targets that, ultimately, are of little value, Dr. Michor added.; d9 d7 D. h+ ^( L0 Y
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There are a lot of fundamental questions that remain about cancer stem cells, Dr. Morrison emphasized. “The way we think about cancer stem cells will change dramatically during the next five years. Cancer is so endlessly resourceful.”作者: luckyfool 时间: 2010-3-29 17:54
这个……很强大 学习了作者: flyingdream 时间: 2010-4-2 11:43
的确强大作者: lixiaoxu 时间: 2010-5-6 11:10
如果真是这样，那我岂不是要out了。作者: hcoohboy 时间: 2010-5-6 20:07
本帖最后由 hcoohboy 于 2010-5-6 20:14 编辑 : Z- z1 M4 s5 K* M 4 N0 Y: n! j0 O# e% y9 T不用Cancer stem cells是为了更严谨，我没看到能够彻底否定这个理论的文章，除非他把每一种肿瘤模型都做一下，Morrison的文章是这一篇：Quintana, E., M. Shackleton, M. Sabel, D.Fullen, T.M. Johnson, and S.J. Morrison. 2008. Efficient tumor formation by single human melanoma cells. Nature 456:593-598. 7 |" T2 x' y0 {2 s黑色素瘤可能只是个特例，我觉得。( v0 Z8 v( g6 {. o( T
现在文章里用tumor-initiating cells 或者是cancer stem-like cells。 + `# M, W, g$ \我觉得整个否定CSCs理论几乎不太可能，只是CSCs的origin有待商榷，现在有两种主要观点：(1)transformation of normal stem cells; (2)de-differentiation of cancer cells under radio/chemo stress.作者: lsp_318 时间: 2011-1-10 23:55
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