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主要收集了2007至今结直肠癌干细胞研究的文献和综述,与大家分享。% Z1 h' U& V! ~6 ]4 M) q6 H
% N9 P- t! y( S$ A }$ q8 ^1 P. t1 J【1】 2006年底nature同期发布两篇关于结直肠癌干细胞的论文
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+ l# H& @ ^' j% n. ]Nature. 2007 Jan 4;445(7123):106-10. Epub 2006 Nov 19.! Q1 b2 u* _6 }% Y. k
A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.* ?$ q: T- X2 ]& u. t$ u
O'Brien CA, Pollett A, Gallinger S, Dick JE.
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Division of Cell and Molecular Biology, University Health Network, Toronto, Ontario, M5G 1L7, Canada.
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Abstract8 q2 W4 f# m' W/ K4 f; [
Colon cancer is one of the best-understood neoplasms from a genetic perspective, yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies. What has yet to be established is whether every colon cancer cell possesses the potential to initiate and sustain tumour growth, or whether the tumour is hierarchically organized so that only a subset of cells--cancer stem cells--possess such potential. Here we use renal capsule transplantation in immunodeficient NOD/SCID mice to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133+; the CD133- cells that comprised the majority of the tumour were unable to initiate tumour growth. We calculated by limiting dilution analysis that there was one CC-IC in 5.7 x 10(4) unfractionated tumour cells, whereas there was one CC-IC in 262 CD133+ cells, representing >200-fold enrichment. CC-ICs within the CD133+ population were able to maintain themselves as well as differentiate and re-establish tumour heterogeneity upon serial transplantation. The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem cells.9 B$ A) A$ p' @: l- V$ l1 [# O
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Nature. 2007 Jan 4;445(7123):111-5. Epub 2006 Nov 19.
! U$ g( ]2 Z2 U$ ~7 DIdentification and expansion of human colon-cancer-initiating cells.
. }! v. D: ]% i& yRicci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R.
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Department of Hematology and Oncology, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.0 [9 t n+ J. r) F, ~; s
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Abstract: y) `: o0 ?5 T& p- T" H
Colon carcinoma is the second most common cause of death from cancer. The isolation and characterization of tumorigenic colon cancer cells may help to devise novel diagnostic and therapeutic procedures. Although there is increasing evidence that a rare population of undifferentiated cells is responsible for tumour formation and maintenance, this has not been explored for colorectal cancer. Here, we show that tumorigenic cells in colon cancer are included in the high-density CD133+ population, which accounts for about 2.5% of the tumour cells. Subcutaneous injection of colon cancer CD133+ cells readily reproduced the original tumour in immunodeficient mice, whereas CD133- cells did not form tumours. Such tumours were serially transplanted for several generations, in each of which we observed progressively faster tumour growth without significant phenotypic alterations. Unlike CD133- cells, CD133+ colon cancer cells grew exponentially for more than one year in vitro as undifferentiated tumour spheres in serum-free medium, maintaining the ability to engraft and reproduce the same morphological and antigenic pattern of the original tumour. We conclude that colorectal cancer is created and propagated by a small number of undifferentiated tumorigenic CD133+ cells, which should therefore be the target of future therapies.
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【2】2007年PNAS发布了CSC大牛Clarke MF关于结直肠癌干细胞的论文
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% n! U& G: M. a9 M, E3 O4 xProc Natl Acad Sci U S A. 2007 Jun 12;104(24):10158-63. Epub 2007 Jun 4.* B) J) O' B# X/ X+ i0 H
Phenotypic characterization of human colorectal cancer stem cells.( K* k% v6 x, g4 O: c
Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF.1 l2 I- l% w7 r) [" d
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Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.) u: q3 o# F7 m% t
1 C1 M: C- O5 ^4 o/ ?2 zAbstract; a) T- u, K: ?" s V
Recent observations indicate that, in several types of human cancer, only a phenotypic subset of cancer cells within each tumor is capable of initiating tumor growth. This functional subset of cancer cells is operationally defined as the "cancer stem cell" (CSC) subset. Here we developed a CSC model for the study of human colorectal cancer (CRC). Solid CRC tissues, either primary tissues collected from surgical specimens or xenografts established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, were disaggregated into single-cell suspensions and analyzed by flow cytometry. Surface markers that displayed intratumor heterogeneous expression among epithelial cancer cells were selected for cell sorting and tumorigenicity experiments. Individual phenotypic cancer cell subsets were purified, and their tumor-initiating properties were investigated by injection in NOD/SCID mice. Our observations indicate that, in six of six human CRC tested, the ability to engraft in vivo in immunodeficient mice was restricted to a minority subpopulation of epithelial cell adhesion molecule (EpCAM)(high)/CD44+ epithelial cells. Tumors originated from EpCAM(high)/CD44+ cells maintained a differentiated phenotype and reproduced the full morphologic and phenotypic heterogeneity of their parental lesions. Analysis of the surface molecule repertoire of EpCAM(high)/CD44+ cells led to the identification of CD166 as an additional differentially expressed marker, useful for CSC isolation in three of three CRC tested. These results validate the stem cell working model in human CRC and provide a highly robust surface marker profile for CRC stem cell isolation.
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7 b( Y6 d8 Y# G9 Y: m【3】2007年 cell stem cell 再发结直肠癌干细胞论文5 t- f2 ?, l; k1 m
Cell Stem Cell. 2007 Oct 11;1(4):389-402.9 p/ R3 I* _/ ^* E* r" o# ]7 a: d2 B
Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4.
! Q5 c& s2 N+ Q1 STodaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, Stassi G.% ]0 |9 B* l2 y M' T
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5 }" A4 V" n1 M( x6 q2 BDepartment of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, 90127 Palermo, Italy.
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Abstract
; V9 n0 X8 E8 L6 @( Z7 ^ SA novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The CD133(+) cells grow in vitro as undifferentiated tumor spheroids, and they are both necessary and sufficient to initiate tumor growth in immunodeficient mice. Xenografts resemble the original human tumor maintaining the rare subpopulation of tumorigenic CD133(+) cells. Further analysis revealed that the CD133(+) cells produce and utilize IL-4 to protect themselves from apoptosis. Consistently, treatment with IL-4Ralpha antagonist or anti-IL-4 neutralizing antibody strongly enhances the antitumor efficacy of standard chemotherapeutic drugs through selective sensitization of CD133(+) cells. Our data suggest that colon tumor growth is dictated by stem-like cells that are treatment resistant due to the autocrine production of IL-4.
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【4】2008年JCI发布一篇论文对CD133作为结肠癌干细胞标记物提出质疑。5 y' T0 j/ K# ~# J, Y3 W
J Clin Invest. 2008 Jun;118(6):2111-20.
) c3 h0 T6 B* L/ K3 OCD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors./ z, [% W( A# b4 w9 J' J/ ~; h! w
Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, D'Angelica M, Kemeny N, Lyden D, Rafii S.
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# g6 z, s. ]% b7 \( tHoward Hughes Medical Institute, Ansary Center for Stem Cell Therapeutics, and Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, USA.) l- l2 p0 i: G# \8 p( ^
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Abstract
* \! f7 M6 n% L* v& X6 aColon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10-/-CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133- population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133- metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133- cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24-), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133(- )subset, which is also capable of tumor initiation in NOD/SCID mice.
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【5】2008年年底nature再次同期发布两篇结直肠癌干细胞论文/ |# j& S# z; f. f. |* f
Nature. 2009 Jan 29;457(7229):608-11. Epub 2008 Dec 17., Y9 D. o' ?% Q$ Z# |& v" _3 @( C
Crypt stem cells as the cells-of-origin of intestinal cancer.
* Y B% D( G" V3 n; fBarker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H(胃肠道肿瘤干细胞大牛).3 C0 @9 L& E1 {% ~; K* t' b1 s3 k
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5 J u8 h& f$ ]; X) x/ m3 g- U4 ?Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht & University Medical Centre Utrecht, Netherlands.& e' h2 E. Z) r) @
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Abstract! H# X* |) Z# z$ ?4 q7 w: D
Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeat containing G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem cells. Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The distribution of Lgr5(+) cells within stem-cell-derived adenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.
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1 g( x1 ?7 e+ x3 DNature. 2009 Jan 29;457(7229):603-7. Epub 2008 Dec 17.! w/ J4 N- s6 k& Y% y
Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation.
; m2 K- ^, |0 B! O) \, n- qZhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, Poppleton H, Zakharenko S, Ellison DW, Gilbertson RJ.
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8 E" H8 T$ R1 N; r" {; [% A" ODepartment of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA." \1 F6 a3 O+ v0 \: P) o$ u& t; @
! Z( t4 D i& }% }6 ^Abstract/ m9 a. h+ H+ m+ g5 Z, s/ s0 H
Cancer stem cells are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, for example, prominin 1 (PROM1, also called CD133). What remains unclear is whether cancer stem cells are the direct progeny of mutated stem cells or more mature cells that reacquire stem cell properties during tumour formation. Answering this question will require knowledge of whether normal stem cells are susceptible to cancer-causing mutations; however, this has proved difficult to test because the identity of most adult tissue stem cells is not known. Here, using an inducible Cre, nuclear LacZ reporter allele knocked into the Prom1 locus (Prom1(C-L)), we show that Prom1 is expressed in a variety of developing and adult tissues. Lineage-tracing studies of adult Prom1(+/C-L) mice containing the Rosa26-YFP reporter allele showed that Prom1(+) cells are located at the base of crypts in the small intestine, co-express Lgr5 (ref. 2), generate the entire intestinal epithelium, and are therefore the small intestinal stem cell. Prom1 was reported recently to mark cancer stem cells of human intestinal tumours that arise frequently as a consequence of aberrant wingless (Wnt) signalling. Activation of endogenous Wnt signalling in Prom1(+/C-L) mice containing a Cre-dependent mutant allele of beta-catenin (Ctnnb1(lox(ex3))) resulted in a gross disruption of crypt architecture and a disproportionate expansion of Prom1(+) cells at the crypt base. Lineage tracing demonstrated that the progeny of these cells replaced the mucosa of the entire small intestine with neoplastic tissue that was characterized by focal high-grade intraepithelial neoplasia and crypt adenoma formation. Although all neoplastic cells arose from Prom1(+) cells in these mice, only 7% of tumour cells retained Prom1 expression. Our data indicate that Prom1 marks stem cells in the adult small intestine that are susceptible to transformation into tumours retaining a fraction of mutant Prom1(+) tumour cells.
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& P4 y3 g3 k/ Q【6】2008年cancer research和PNAS上的论文,从不同角度研究结直肠癌干细胞。
0 Q+ s) E) s( m+ X5 U) {Cancer Res. 2008 Sep 1;68(17):6932-41.
9 X+ q0 A& h" }. T" v( x! }% vA stochastic model for cancer stem cell origin in metastatic colon cancer.* A% \( _7 T: A4 _& B* C
Odoux C, Fohrer H, Hoppo T, Guzik L, Stolz DB, Lewis DW, Gollin SM, Gamblin TC, Geller DA, Lagasse E.
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McGowan Institute for Regenerative Medicine, Department of Pathology, University of Pittsburgh Medical School, 100 Technology Drive, Suite 200, Pittsburgh PA, 15219-3130, USA.
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Abstract
, o6 H0 Z& ^, x% t8 S! w5 \Human cancers have been found to include transformed stem cells that may drive cancer progression to metastasis. Here, we report that metastatic colon cancer contains clonally derived tumor cells with all of the critical properties expected of stem cells, including self-renewal and the ability to differentiate into mature colon cells. Additionally, when injected into mice, these cells initiated tumors that closely resemble human cancer. Karyotype analyses of parental and clonally derived tumor cells expressed many consistent (clonal) along with unique chromosomal aberrations, suggesting the presence of chromosomal instability in the cancer stem cells. Thus, this new model for cancer origin and metastatic progression includes features of both the hierarchical model for cancerous stem cells and the stochastic model, driven by the observation of chromosomal instability.
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+ O, P+ N1 f! A1 I3 t8 [, NProc Natl Acad Sci U S A. 2008 Sep 9;105(36):13427-32. Epub 2008 Sep 2.
& D- P1 F) q$ ]- dSingle-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity.
* W Z8 e6 a; z( Y" PVermeulen L, Todaro M, de Sousa Mello F, Sprick MR, Kemper K, Perez Alea M, Richel DJ, Stassi G, Medema JP./ ~& G F0 V/ R+ l+ a, {
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3 {! z, y+ ~4 K' V: ~1 X) nLaboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Meibergdreef 9 1105 AZ, Amsterdam, The Netherlands.
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Abstract) K k0 u; @, x
Colon carcinoma is one of the leading causes of death from cancer and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, it was reported that a population of undifferentiated cells from a primary tumor, so-called cancer stem cells (CSC), can reconstitute the original tumor on xenotransplantation. Here, we show that spheroid cultures of these colon CSCs contain expression of CD133, CD166, CD44, CD29, CD24, Lgr5, and nuclear beta-catenin, which have all been suggested to mark the (cancer) stem cell population. More importantly, by using these spheroid cultures or freshly isolated tumor cells from multiple colon carcinomas, we now provide compelling evidence to indicate that the capacity to propagate a tumor with all differentiated progeny resides in a single CSC. Single-cell-cloned CSCs can form an adenocarcinoma on xenotransplantation but do not generate the stroma within these tumors. Moreover, they can self-renew and are capable of multilineage differentiation. Further analysis indicated that the lineage decision is dictated by phosphoinositide 3-kinase (PI3K) signaling in CSCs. These data support the hypothesis that tumor hierarchy can be traced back to a single CSC that contains multilineage differentiation capacity, and provides clues to the regulation of differentiation in colon cancers in vivo.
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