| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cell and Tumor Biology |
1 Yorkshire Cancer Research Unit, Department of Biology, University of York and 2 Department of Urology, York Hospital, National Health Service Trust, York, United Kingdom
Requests for reprints: Anne T. Collins, Yorkshire Cancer Research Unit, Department of Biology, University of York, Heslington, York YO31 5D, United Kingdom. Phone: 44-1904-328708; Fax: 44-1904-328710; E-mail: ac43{at}york.ac.uk.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2ß1hi/CD133+ phenotype, and we have exploited these markers to isolate cells from a series of prostate tumors with differing Gleason grade and metastatic states. Approximately 0.1% of cells in any tumor expressed this phenotype, and there was no correlation between the number of CD44+/2ß1hi/CD133+ cells and tumor grade. The identification of a prostate cancer stem cell provides a powerful tool to investigate the tumorigenic process and to develop therapies targeted to the stem cell. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We have pioneered the identification and isolation of stem cells from human prostate epithelia based on high surface expression of integrin 2ß1 (10) and CD133 (11). As tumor cells might be expected to share some of their antigenic properties with tissue stem cells from the same organ (5), we have applied the same techniques used to isolate normal prostate epithelial stem cells to the analysis of the tumorigenic cells in human prostate cancers. We report here the identification and characterization of cells from primary and metastatic prostate tumors that have cancer stem cell characteristics, namely a capacity for extensive proliferation, self-renewal, differentiation, and invasion.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2ß1hi/CD133+ cells were isolated from the tissue, as described previously for normal prostate epithelium (11), and were subsequently placed in long-term culture from four tumor samples and one benign biopsy. Cultures were maintained in complete keratinocyte growth medium [keratinocyte serum-free medium with epidermal growth factor (EGF) and bovine pituitary extract; Invitrogen, Paisley, Scotland]. The medium was also supplemented with 2 ng/mL of leukemia inhibitory factor (LIF; Sigma, Poole, United Kingdom), 2 ng/mL of stem cell factor (Sigma), and 100 ng/mL of cholera toxin (Sigma).
Cultures were also derived from two lymph node metastasis of the prostate but initially from an unselected epithelial population. However, after expansion in culture, CD44/2ß1hi/CD133+ were isolated and cultures were derived.
Colony-forming and long-term serial culture assays. The potential of the tumor populations, CD44+/2ß1hi/CD133+ (stem cells), CD44+/2ß1hi/CD133– (transit amplifying population), and CD44+/2ß1low (committed basal population), to form colonies was compared with the unselected tumor population. Briefly, the above phenotypes were counted and plated on collagen-coated (BD-Biocoat) plates (BD Biosciences, Oxford, United Kingdom) for the determination of both colony-forming efficiency and self-renewal. Colonies were counted, ring-cloned (after 28 days if they contained >32 cells), and replated into individual wells of a 24-well plate. As the number of cells selected was small, irradiated (60 Gy) STO (mouse embryonic fibroblasts) cells were added as feeders. For the long-term serial culture assays, used to determine the proliferative potential of selected phenotypes, cells were passaged continuously. At each passage, the number of cells generated by each fraction was determined. The cumulative total cell output from the initial 103 cells was calculated at the end of the experiment, assuming that all cells from each passage had been replated.
Anchorage-independent growth was also assessed in methylcellulose (Miltenyi Biotec Ltd., Bisley, Surrey, United Kingdom). Briefly, the above phenotypes were placed in complete methylcellulose (supplemented with EGF, bovine pituitary extract, stem cell factor, LIF, and cholera toxin at the concentrations used for complete keratinocyte serum-free medium) and the number of surviving cells was counted after 28 days. The results were subjected to a paired t test to determine statistical significance.
Immunofluorescent staining of CD44+/2ß1hi/CD133+ cells. CD44+/2ß1hi/CD133+ cells were selected directly from disaggregated tumor tissue or cultured cells from tumors before processing for dual-color imaging under confocal microscopy by fixation in ice-cold methanol for 20 minutes and permeabilization in 0.4% Triton X-100 (Sigma) containing 0.3% normal goat serum (NGS) for 10 minutes. After blocking (1:5 dilution of NGS in TBS for 10 minutes), cells were incubated with antibodies against keratins 1, 5, 10, and 14 (clone 34ßE12, DakoCytomation, Ely, Cambridgeshire, United Kingdom); keratin 5 (clone RCK103, BD PharMingen, Oxford, England); keratin 14 (clone LL002, Serotec Ltd., Oxford, England); keratin 19 (clone RCK 108, DakoCytomation); keratin 18 (clone CY-90; Sigma); c-Met (clone 8F11, Vector Laboratories, Inc., Peterborough, United Kingdom); prostatic acid phosphatase (clone PASE/4LJ, DakoCytomation); androgen receptor (clone AR27, Novocastra Laboratories Ltd., Newcastle upon Tyne, United Kingdom); and prostate-specific stem cell antigen (clone 2399, kindly donated by Genentech, Inc., San Franscisco, CA) or a nonspecific isotype control for 1 hour. Appropriate positive control cells were stained in parallel for each antibody used for CD133+ cell phenotyping. After washing (3x TBS), cells were further probed with FITC-tagged secondary antibody. Cells were mounted in the antiphotobleaching medium Vectashield containing 4',6-diamidino-2-phenylindole (DAPI; Vector Laboratories).
Invasion activity assay in Matrigel. The ability of epithelial cells to migrate through Matrigel was determined by the modified Boyden-chamber method (12). Briefly, tumor cells, derived initially from CD133+-selected populations from patients with prostate cancer, were plated onto Matrigel-coated 8 µm filters. Conditioned medium from prostate stromal cultures (13) was used as a chemoattractant. Cells invading through Matrigel and filters were counted 48 hours after plating. Epithelial cells from benign prostate and PNT1a (an immortalized cell line from benign prostate) were used as negative controls. The positive controls were PC3M (metastatic prostate cancer cell line) and MCF7 (metastatic breast cancer cell line). The results were subjected to a paired t test to determine statistical significance.
Differentiation of adult CD44+/2ß1hi/CD133+ isolated from prostate tumors. CD44+/2ß1hi/CD133+ cells were isolated from tumor biopsies and cultured for up to 21 days in RPMI 1640 (Invitrogen), supplemented with 10% FCS and 10–9 mol/L dihydrotestosterone. Cells were subsequently processed for dual-color staining flow cytometry. Dual staining was done on cells fixed and permeabilized in 1% saponin (Sigma). Cells were separated on a DakoCytomation CyAn high-performance flow cytometer and analyzed using DakoCytomation Summit version 3.3 software (DakoCytomation).
Genotype analysis of tumor cells. To confirm the identity of the cultures from primary tissues, 40 ng of DNA extracted from the cultured cells derived by CD133 selection was compared with DNA extracted from peripheral blood lymphocytes (PBL) taken from the same patient (14). In some cases, a third comparison, with DNA extracted from serial frozen tissue sections, was also used. Primers spanning five highly polymorphic microsatellites (D8S262, D8S264, D8S560, D8S592, and D16S422), one of which was labeled with a Beckman dye (D2, D3, or D4), were used in a PCR as previously described (14). Touchdown PCR to take account of varying base pair composition was used (10 minutes at 94°C; followed by 16 touchdown cycles of 94°C/45 seconds, 60-52°C/45 seconds, 72°C/30 seconds; then 16 cycles of 94°C/45 seconds; 52°C/45 seconds, 72°C/30 seconds; and finally 72°C/7 minutes). Analysis of the labeled fragments was accomplished on a Beckman Coulter CEQ8000 and proprietary CEQ fragment analysis software to accurately size and quantify alleles.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2ß1hi/CD133+ cells exhibit a high proliferative potential in vitro. We have previously established that the phenotype 2ß1hi/CD133+ determines normal prostate epithelial stem cells (11). To establish whether 2ß1hi/CD133+ cells were present in prostate tumors, we initially used MACS bead sorting to determine the proportion of CD133-expressing cells in a series of 40 prostate tumors. Regardless of the tumor grade, a small population (ranging from 0.1% to 0.3%) of CD133-expressing cells could be isolated (results not shown) from all tumors tested.
To determine whether tumor 2ß1hi/CD133+ cells were distinct from the bulk population of cancer cells, we next looked at the proliferative properties of six independently derived tumor cultures in vitro. Long-term cultures were established from four primary prostate tumors and two metastatic prostate tumors from this larger series (Table 1). Self-renewal of specific phenotypes was measured by replating primary colonies and subsequently measuring secondary colony-forming efficiency. As shown in Fig. 1A, the CD44+/2ß1hi/CD133+ cells gave rise to 3.7-fold greater numbers of colonies than the total population and this number was significantly greater (P < 0.05) than those formed from either CD44+/2ß1hi/CD133– or CD44+/2ß1low cells. Indeed, 30-fold fewer colonies were founded by the CD44+/2ß1low population compared with the CD133––selected population. There was no significant difference (P > 0.05) between the primary and secondary colony-forming efficiency of the stem cell population, whereas the ability of the transit amplifying population (CD44+/2ß1hi/CD133–) to undergo self-renewal (secondary colony-forming efficiency) was significantly lower than the stem cell population (P < 0.005). Few primary colonies were founded by CD44+/2ß1low cells and the majority was abortive after one to three rounds of cell division. The ability of this population to form secondary colonies was also significantly less than the stem cell population (P < 0.005; 44-fold less secondary colonies founded). Primary colonies were not founded by the secretory luminal (CD44–/CD57+) population.
|
|
2ß1hi/CD133+ cells were capable of extensive proliferation (e.g., generating progeny several orders of magnitude higher that the starting population), cultures were generated from a series of prostate primary and metastatic tumors from a starting population of 103 CD44+/2ß1hi/CD133+ cells (Fig. 1B). The data clearly indicate that tumor cultures derived from CD133+ cells have an enhanced proliferative potential. In contrast, the proliferative potential of CD133+ cells, derived from benign prostate, was much lower and proliferation ceased after 
12 PD. Quantification of CD133 expression, by MACS cell sorting, in long-term cultures of prostate cancer cells ranged from 0.3% to 1.6% (Table 2). Regardless of time in culture, the proportion of CD133-expressing cells remained relatively constant and did not differ significantly from the freshly isolated population (P > 0.05).
|
|
2ß1hi/CD133+ cells, from four separate tumors, showed enhanced survival relative to the unselected tumor cell population (median 3-fold higher) and even greater survival (median 8-fold higher) compared with the more differentiated CD44+/2ß1low cells (Fig. 2B). On isolation of small cell populations, there is a finite possibility of cross-contamination between cultures. Indeed, this seems to have been a common occurrence in various tumor cell banks. To verify the identity of all cultures, a microsatellite analysis using a panel of five highly polymorphic loci was routinely done. Although this was unable to unequivocally confirm the tumor cell origin of the cultured cells, the microsatellite signatures matched cultures to the PBLs (and in some cases the original tissues) of the patient from which the culture was derived. All the long-term cultures were of human origin and did not derive from the irradiated STO feeder cells. Two examples of this (for cultures P434 and P484) with three of five microsatellites are shown in Fig. 3. In two of six cultures (shown for tumor P434 with the microsatellite D8S264), evidence of microsatellite instability was observed but only in the tumor cultures and not in the patient's PBL DNA.
|
2ß1hi/CD133+ cells differentiate to an androgen receptor–positive phenotype similar to prostate cancers in situ. To determine whether the tumor stem cell population was capable of differentiation to a secretory luminal phenotype, we applied conditions previously used to induce differentiation of normal prostate epithelium. As the prostate is an androgen-dependent organ, where the bulk population of tumor cells is responsive to the effects of androgen, cultures were treated with 1 nmol/L dihydrotestosterone in serum-containing medium and the resultant phenotypes were determined by flow cytometry. Immunocytochemical analysis of isolated CD133+ cells (purified either directly from disaggregated tumor samples or after expansion in culture) showed that this small population had a basal phenotype (Fig. 4A). CD133+ cells expressed the high-molecular-weight keratins 5 and 14, as well as keratin 19. Keratin 18 was weakly expressed and only in a minority of the population. c-MET, a marker of the transit-amplifying population (15), and the markers associated with the terminally differentiated cells in the prostate, androgen receptor, and prostatic acid phosphatase were not expressed. We also looked at prostate-specific stem cell antigen expression, which is a marker of intermediate prostate epithelial cells (16) and as expected it was not expressed within the CD133-selected population. Although the expanded tumor cultures were capable of some degree of differentiation under serum-free culture conditions, higher expression levels of the androgen receptor and prostatic acid phosphatase were only achieved after treating the cultures with serum and dihydrotestosterone (Fig. 4B). CD133 expression was also determined under differentiating conditions and was characteristically reduced [by fluorescence-activated cell sorting (FACS) analysis] but not eliminated after serum and dihydrotestosterone treatment in the two cultures examined (Table 3).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2ß1hi/CD133+, can be used to locate and isolate an epithelial stem cell population from normal human prostate (10, 11). The experiments we describe here constitute the first successful attempt to isolate and characterize the cancer stem cell population from human prostate tumors using identical markers. There are three lines of evidence to support that these cells are tumor stem cells: (a) they represent a small fraction of the total cells comprising the tumor, (b) they self-renew and proliferate, and (c) they differentiate to recapitulate the phenotype of the tumor from which they were derived. Regardless of tumor grade, a small population of CD133-expressing cells could be isolated from a large series of prostate tumors, which included metastatic lesions. This proportion of stem cells is in contrast with a recent publication by Singh et al. (7), who reported that brain tumors, particularly high-grade medulloblastomas, contained two orders of magnitude higher numbers of CD133-expressing cells compared with prostate tumors. Nonetheless, the levels of CD133-expressing cells are more consistent with our previous findings with normal prostate epithelial stem cells (11), where the CD133+ cells constitute 1% of the basal population.
There are striking similarities between normal tissue homeostasis and tumorigenesis. Stem cells are functionally defined as self-renewing and multipotent, generating the mature cell types of a particular tissue through differentiation. In malignancies, such as leukemia (5) and breast (6), brain (8), and, more recently, lung (9) cancers, rare cells have been isolated with a remarkable potential for self-renewal. These cells were distinct from the bulk of the tumor in driving tumor growth and maintenance.
We found that only tumor-derived CD133+ cells were capable of self-renewal and extensive proliferation. In contrast, more differentiated phenotypes did not form secondary colonies and a comparison of the proliferative potential of CD133+ cells from benign prostate showed the capacity of tumor-derived CD133+ cells to proliferate extensively in vitro, which is similar to our previous findings with benign prostate (11). Thus, CD133 expression identifies an exclusive subpopulation of prostate tumor cells that are potentially immortal (having undergone >30 PD in culture to date) compared with similar populations of cells from nonmalignant prostate.
Although we acknowledge that the ultimate test of tumorigenicity is transplantation in vivo, we do provide compelling evidence that the CD133-derived cultures were tumorigenic as they were invasive in Matrigel (12) and survived in suspension culture at clonal densities. In our hands, most primary prostate tumor cells do not form large discrete colonies in methylcellulose (if plated at cloning densities), as found with mammary (17) and neural tumors (7).
The cultured cells were, in all cases used for biological characterization, identical by microsatellite analysis to the genotype of the patient from which they were derived. Although insufficient microsatellite markers were used to determine the extent of allelic imbalance, in two cases, microsatellite instability, which has been observed in a proportion of prostate tumor biopsies and associated with prostate cancer recurrence after therapy (18, 19), was detected in the cultured tumor stem cells. A fuller analysis of multiple loci and a detailed assessment of degrees of heritable genetic change by single nucleotide polymorphism analysis, with the Affymetrix 100k single nucleotide polymorphism chip using purified cell populations is currently under way. There is no certainty that the cancer stem cells will show the full extent of chromosomal damage found in previous analyses of prostate tissue DNA, as genetic heterogeneity in a large developing malignant tumor (sufficiently large for such analysis and often containing a significant stromal component) is likely to be great (14, 20).
The cellular origins of prostate cancer are still controversial. It has been suggested that prostate cancers arise from the terminally differentiated luminal cells (21) because the bulk population of tumor cells, in the most common form of prostate cancer, express luminal cell-specific markers (cytokeratins 8 and 18, androgen receptor, prostate-specific antigen, and prostatic acid phosphatase), but lack expression of basal cell markers, such as p63. Other studies suggest that the disease is derived from intermediate progenitors that have acquired the ability to self-renew (22). Xin et al. (23) recently reported that introduction of constitutively active AKT in Sca-1-enriched murine prostate epithelial cells results in the initiation of prostate tumorigenesis. Moreover, Sca-1-sorted cells, enriched for cells with prostate-regenerating activity, showed evidence of both basal and luminal lineage. Our data suggest that prostate tumors originate from basal cells expressing CD133 as this fraction exclusively had the ability to self-renew and differentiate into the mature cell types, which characterize the vast majority of prostate tumors.
By exploiting shared antigen expression between normal and cancer stem cells, we have been able to identify and isolate a population of cells that is highly enriched for a phenotype that is consistent with a cancer stem cell for prostate. With evidence of self-renewal, proliferation, and differentiation that recapitulates the original tumor phenotype, we have defined a class of prostate cancer stem cells that can be prospectively isolated from prostate tumors. These cells form a small subset of the population even after long-term culture. Therefore, we would predict that both tumor heterogeneity and the overall androgen-sensitive phenotype of human prostate cancers is the consequence of differentiation from an androgen receptor–negative stem cell population. Although further in vivo experiments are required to determine whether the tumor-initiating cells are comparable with the in vitro phenotype, this study provides evidence of the origin of prostate cancer from a CD133-enriched cell, that possesses stem cell properties and can serve as targets for the initiation of prostate tumorigenesis and metastasis.
|
Acknowledgments |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Michelle Scaife for assembly of the manuscript, Steve Bryce for DNA samples, and Celina Whalley for technical assistance with microsatellite analysis.
Received 6/13/05. Revised 8/19/05. Accepted 9/ 6/05.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2ß1-integrin expression. J Cell Sci 2001;114:3865–72.This article has been cited by other articles:
|
|
 |
|
  D. J. Mulholland, L. Xin, A. Morim, D. Lawson, O. Witte, and H. Wu Lin-Sca-1+CD49fhigh Stem/Progenitors Are Tumor-Initiating Cells in the Pten-Null Prostate Cancer Model Cancer Res., November 15, 2009; 69(22): 8555 - 8562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Hubbard, A. M. Friel, B. Kumar, L. Zhang, B. R. Rueda, and C. E. Gargett Evidence for Cancer Stem Cells in Human Endometrial Carcinoma Cancer Res., November 1, 2009; 69(21): 8241 - 8248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Bertolini, L. Roz, P. Perego, M. Tortoreto, E. Fontanella, L. Gatti, G. Pratesi, A. Fabbri, F. Andriani, S. Tinelli, et al. Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment PNAS, September 22, 2009; 106(38): 16281 - 16286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Tirino, R. Camerlingo, R. Franco, D. Malanga, A. La Rocca, G. Viglietto, G. Rocco, and G. Pirozzi The role of CD133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer Eur. J. Cardiothorac. Surg., September 1, 2009; 36(3): 446 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Hynes, K. M. Huang, and E. H. Huang REVIEW PAPER: Implications of the "Cancer Stem Cell" Hypothesis on Murine Models of Colon Cancer and Colitis-associated Cancer Vet. Pathol., September 1, 2009; 46(5): 819 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Oda, T. Tian, M. Inoue, J.-i. Ikeda, Y. Qiu, M. Okumura, K. Aozasa, and E. Morii Tumorigenic Role of Orphan Nuclear Receptor NR0B1 in Lung Adenocarcinoma Am. J. Pathol., September 1, 2009; 175(3): 1235 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Short and D. T. Curiel Oncolytic adenoviruses targeted to cancer stem cells Mol. Cancer Ther., August 1, 2009; 8(8): 2096 - 2102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schmidt, M. E. Scheulen, C. Dittrich, P. Obrist, N. Marschner, L. Dirix, M. Schmidt, D. Ruttinger, M. Schuler, C. Reinhardt, et al. An open-label, randomized phase II study of adecatumumab, a fully human anti-EpCAM antibody, as monotherapy in patients with metastatic breast cancer Ann. Onc., July 24, 2009; (2009) mdp314v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rutella, G. Bonanno, A. Procoli, A. Mariotti, M. Corallo, M. G. Prisco, A. Eramo, C. Napoletano, D. Gallo, A. Perillo, et al. Cells with Characteristics of Cancer Stem/Progenitor Cells Express the CD133 Antigen in Human Endometrial Tumors Clin. Cancer Res., July 1, 2009; 15(13): 4299 - 4311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li and J. Kim Molecular Profiles of Finasteride Effects on Prostate Carcinogenesis Cancer Prevention Research, June 1, 2009; 2(6): 518 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Zhuang, Z. Qin, and Z. Liang The role of autophagy in sensitizing malignant glioma cells to radiation therapy Acta Biochim Biophys Sin, May 1, 2009; 41(5): 341 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yanagisawa, I. Kadouchi, K. Yokomori, M. Hirose, M. Hakozaki, H. Hojo, K. Maeda, E. Kobayashi, and T. Murakami Identification and Metastatic Potential of Tumor-Initiating Cells in Malignant Rhabdoid Tumor of the Kidney Clin. Cancer Res., May 1, 2009; 15(9): 3014 - 3022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Vlashi, K. Kim, C. Lagadec, L. D. Donna, J. T. McDonald, M. Eghbali, J. W. Sayre, E. Stefani, W. McBride, and F. Pajonk In Vivo Imaging, Tracking, and Targeting of Cancer Stem Cells J Natl Cancer Inst, March 4, 2009; 101(5): 350 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Hongling Du and H. S. Taylor Reviews: Stem Cells and Female Reproduction Reproductive Sciences, February 1, 2009; 16(2): 126 - 139. [Abstract] [PDF]
|
|
|
|
|
|
S. Ando, R. Abe, M. Sasaki, J. Murata, D. Inokuma, and H. Shimizu Bone Marrow-Derived Cells Are Not the Origin of the Cancer Stem Cells in Ultraviolet-Induced Skin Cancer Am. J. Pathol., February 1, 2009; 174(2): 595 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. L. BOTCHKINA, R. A. ROWEHL, D. E. RIVADENEIRA, M. S. KARPEH JR., H. CRAWFORD, A. DUFOUR, J. JU, Y. WANG, Y. LEYFMAN, and G. I. BOTCHKINA Phenotypic Subpopulations of Metastatic Colon Cancer Stem Cells: Genomic Analysis Cancer Genomics Proteomics, January 1, 2009; 6(1): 19 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Miele, N. Takebe, and S. P. Ivy The Cancer Stem Cell Hypothesis, Embryonic Signaling Pathways, and Therapeutics: Targeting an Elusive Concept ASCO Educational Book, January 1, 2009; 2009(1): 145 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Goldstein, D. A. Lawson, D. Cheng, W. Sun, I. P. Garraway, and O. N. Witte Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics PNAS, December 30, 2008; 105(52): 20882 - 20887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, Y. Lu, J. Wang, A. E. Koch, J. Zhang, and R. S. Taichman CXCR6 Induces Prostate Cancer Progression by the AKT/Mammalian Target of Rapamycin Signaling Pathway Cancer Res., December 15, 2008; 68(24): 10367 - 10377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Vander Griend, W. L. Karthaus, S. Dalrymple, A. Meeker, A. M. DeMarzo, and J. T. Isaacs The Role of CD133 in Normal Human Prostate Stem Cells and Malignant Cancer-Initiating Cells Cancer Res., December 1, 2008; 68(23): 9703 - 9711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.U. Lukacs, D.A. Lawson, L. Xin, Y. Zong, I. Garraway, A.S. Goldstein, S. Memarzadeh, and O.N. Witte Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression Cold Spring Harb Symp Quant Biol, November 6, 2008; (2008) sqb.2008.73.012v1. [Abstract] [PDF]
|
|
|
|
|
|
I. Zucchi, S. Astigiano, G. Bertalot, S. Sanzone, C. Cocola, P. Pelucchi, G. Bertoli, M. Stehling, O. Barbieri, A. Albertini, et al. Distinct populations of tumor-initiating cells derived from a tumor generated by rat mammary cancer stem cells PNAS, November 4, 2008; 105(44): 16940 - 16945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Du, H. Wang, L. He, J. Zhang, B. Ni, X. Wang, H. Jin, N. Cahuzac, M. Mehrpour, Y. Lu, et al. CD44 is of Functional Importance for Colorectal Cancer Stem Cells Clin. Cancer Res., November 1, 2008; 14(21): 6751 - 6760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Kirkland and H. Ying {alpha}2{beta}1 Integrin Regulates Lineage Commitment in Multipotent Human Colorectal Cancer Cells J. Biol. Chem., October 10, 2008; 283(41): 27612 - 27619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Yi, H.-C. Tsai, S. C. Glockner, S. Lin, J. E. Ohm, H. Easwaran, C. D. James, J. F. Costello, G. Riggins, C. G. Eberhart, et al. Abnormal DNA Methylation of CD133 in Colorectal and Glioblastoma Tumors Cancer Res., October 1, 2008; 68(19): 8094 - 8103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Bussolati, S. Bruno, C. Grange, U. Ferrando, and G. Camussi Identification of a tumor-initiating stem cell population in human renal carcinomas FASEB J, October 1, 2008; 22(10): 3696 - 3705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Simeone Pancreatic Cancer Stem Cells: Implications for the Treatment of Pancreatic Cancer Clin. Cancer Res., September 15, 2008; 14(18): 5646 - 5648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. Goel, J. Li, S. Kogan, and L. R Languino Integrins in prostate cancer progression Endocr. Relat. Cancer, September 1, 2008; 15(3): 657 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Risbridger and R. A. Taylor Regulation of Prostatic Stem Cells by Stromal Niche in Health and Disease Endocrinology, September 1, 2008; 149(9): 4303 - 4306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-W. Chang, C. H. Lee, P. Lee, J. Lin, C.-W. Hsu, J.-T. Hung, J.-J. Lin, J.-C. Yu, L.-e. Shao, J. Yu, et al. Expression of Globo H and SSEA3 in breast cancer stem cells and the involvement of fucosyl transferases 1 and 2 in Globo H synthesis PNAS, August 19, 2008; 105(33): 11667 - 11672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-i. Ikeda, E. Morii, Y. Liu, Y. Qiu, N. Nakamichi, R. Jokoji, Y. Miyoshi, S. Noguchi, and K. Aozasa Prognostic Significance of CD55 Expression in Breast Cancer Clin. Cancer Res., August 1, 2008; 14(15): 4780 - 4786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xiao, Y. Ye, K. Yearsley, S. Jones, and S. H. Barsky The Lymphovascular Embolus of Inflammatory Breast Cancer Expresses a Stem Cell-Like Phenotype Am. J. Pathol., August 1, 2008; 173(2): 561 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Maitland and A. T. Collins Prostate Cancer Stem Cells: A New Target for Therapy J. Clin. Oncol., June 10, 2008; 26(17): 2862 - 2870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E.P. Prince and L. E. Ailles Cancer Stem Cells in Head and Neck Squamous Cell Cancer J. Clin. Oncol., June 10, 2008; 26(17): 2871 - 2875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Takaishi, T. Okumura, and T. C. Wang Gastric Cancer Stem Cells J. Clin. Oncol., June 10, 2008; 26(17): 2876 - 2882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Peacock and D. N. Watkins Cancer Stem Cells and the Ontogeny of Lung Cancer J. Clin. Oncol., June 10, 2008; 26(17): 2883 - 2889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Hart and W. S. El-Deiry Invincible, but Not Invisible: Imaging Approaches Toward In Vivo Detection of Cancer Stem Cells J. Clin. Oncol., June 10, 2008; 26(17): 2901 - 2910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhang, C. Balch, M. W. Chan, H.-C. Lai, D. Matei, J. M. Schilder, P. S. Yan, T. H-M. Huang, and K. P. Nephew Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors Cancer Res., June 1, 2008; 68(11): 4311 - 4320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L Ricci-Vitiani, A Pagliuca, E Palio, A Zeuner, and R De Maria Colon cancer stem cells Gut, April 1, 2008; 57(4): 538 - 548. [Full Text] [PDF]
|
|
|
|
|
|
K. Engelmann, H. Shen, and O. J. Finn MCF7 Side Population Cells with Characteristics of Cancer Stem/Progenitor Cells Express the Tumor Antigen MUC1 Cancer Res., April 1, 2008; 68(7): 2419 - 2426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mimeault, P. P. Mehta, R. Hauke, and S. K. Batra Functions of Normal and Malignant Prostatic Stem/Progenitor Cells in Tissue Regeneration and Cancer Progression and Novel Targeting Therapies Endocr. Rev., April 1, 2008; 29(2): 234 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Bera, D. N. R. Veeramachaneni, and K. Pandher Characterization of a Biphasic Neoplasm in a Madagascar Tree Boa (Sanzinia madagascariensis) Vet. Pathol., March 1, 2008; 45(2): 259 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, Y. Shiozawa, J. Wang, Y. Wang, Y. Jung, K. J. Pienta, R. Mehra, R. Loberg, and R. S. Taichman The Role of CXCR7/RDC1 as a Chemokine Receptor for CXCL12/SDF-1 in Prostate Cancer J. Biol. Chem., February 15, 2008; 283(7): 4283 - 4294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liu, C. Ginestier, E. Charafe-Jauffret, H. Foco, C. G. Kleer, S. D. Merajver, G. Dontu, and M. S. Wicha BRCA1 regulates human mammary stem/progenitor cell fate PNAS, February 5, 2008; 105(5): 1680 - 1685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. B Dirks Brain tumour stem cells: the undercurrents of human brain cancer and their relationship to neural stem cells Phil Trans R Soc B, January 12, 2008; 363(1489): 139 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Zeppernick, R. Ahmadi, B. Campos, C. Dictus, B. M. Helmke, N. Becker, P. Lichter, A. Unterberg, B. Radlwimmer, and C. C. Herold-Mende Stem Cell Marker CD133 Affects Clinical Outcome in Glioma Patients Clin. Cancer Res., January 1, 2008; 14(1): 123 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tang, B. T. Ang, and S. Pervaiz Cancer stem cell: target for anti-cancer therapy FASEB J, December 1, 2007; 21(14): 3777 - 3785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Reiner, A. de las Pozas, R. Parrondo, and C. Perez-Stable Progression of Prostate Cancer from a Subset of p63-Positive Basal Epithelial Cells in FG/Tag Transgenic Mice Mol. Cancer Res., November 1, 2007; 5(11): 1171 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Kern and D. Shibata The Fuzzy Math of Solid Tumor Stem Cells: A Perspective Cancer Res., October 1, 2007; 67(19): 8985 - 8988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mimeault and S. K. Batra Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies Ann. Onc., October 1, 2007; 18(10): 1605 - 1619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jiang, C. Gomez-Manzano, H. Aoki, M. M. Alonso, S. Kondo, F. McCormick, J. Xu, Y. Kondo, B. N. Bekele, H. Colman, et al. Examination of the Therapeutic Potential of Delta-24-RGD in Brain Tumor Stem Cells: Role of Autophagic Cell Death J Natl Cancer Inst, September 19, 2007; 99(18): 1410 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Buijs, C. A. Rentsch, G. van der Horst, P. G.M. van Overveld, A. Wetterwald, R. Schwaninger, N. V. Henriquez, P. ten Dijke, F. Borovecki, R. Markwalder, et al. BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo Am. J. Pathol., September 1, 2007; 171(3): 1047 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Patrawala, T. Calhoun-Davis, R. Schneider-Broussard, and D. G. Tang Hierarchical Organization of Prostate Cancer Cells in Xenograft Tumors: The CD44+{alpha}2{beta}1+ Cell Population Is Enriched in Tumor-Initiating Cells Cancer Res., July 15, 2007; 67(14): 6796 - 6805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Yu, X. Sun, Y. Qiu, J. Zhou, Y. Wu, L. Zhuang, J. Chen, and Y. Ding Identification and Clinical Significance of Mobilized Endothelial Progenitor Cells in Tumor Vasculogenesis of Hepatocellular Carcinoma Clin. Cancer Res., July 1, 2007; 13(13): 3814 - 3824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. V. Pfenninger, T. Roschupkina, F. Hertwig, D. Kottwitz, E. Englund, J. Bengzon, S. E. Jacobsen, and U. A. Nuber CD133 Is Not Present on Neurogenic Astrocytes in the Adult Subventricular Zone, but on Embryonic Neural Stem Cells, Ependymal Cells, and Glioblastoma Cells Cancer Res., June 15, 2007; 67(12): 5727 - 5736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gu, J. Yuan, M. Wills, and S. Kasper Prostate Cancer Cells with Stem Cell Characteristics Reconstitute the Original Human Tumor In vivo Cancer Res., May 15, 2007; 67(10): 4807 - 4815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Farnie, R. B. Clarke, K. Spence, N. Pinnock, K. Brennan, N. G. Anderson, and N. J. Bundred Novel Cell Culture Technique for Primary Ductal Carcinoma In Situ: Role of Notch and Epidermal Growth Factor Receptor Signaling Pathways J Natl Cancer Inst, April 18, 2007; 99(8): 616 - 627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, L.-P. Guo, L.-Z. Chen, Y.-X. Zeng, and S. H. Lu Identification of Cancer Stem Cell-Like Side Population Cells in Human Nasopharyngeal Carcinoma Cell Line Cancer Res., April 15, 2007; 67(8): 3716 - 3724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Miki, B. Furusato, H. Li, Y. Gu, H. Takahashi, S. Egawa, I. A. Sesterhenn, D. G. McLeod, S. Srivastava, and J. S. Rhim Identification of Putative Stem Cell Markers, CD133 and CXCR4, in hTERT-Immortalized Primary Nonmalignant and Malignant Tumor-Derived Human Prostate Epithelial Cell Lines and in Prostate Cancer Specimens Cancer Res., April 1, 2007; 67(7): 3153 - 3161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Flynn and D. S. Kaufman Donor cell leukemia: insight into cancer stem cells and the stem cell niche Blood, April 1, 2007; 109(7): 2688 - 2692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mimeault, S. L. Johansson, G. Vankatraman, E. Moore, J.-P. Henichart, P. Depreux, M.-F. Lin, and S. K. Batra Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells Mol. Cancer Ther., March 1, 2007; 6(3): 967 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Phillips, W. H. McBride, and F. Pajonk The Response of CD24-/low/CD44+ Breast Cancer-Initiating Cells to Radiation J Natl Cancer Inst, December 20, 2006; 98(24): 1777 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bruno, B. Bussolati, C. Grange, F. Collino, M. E. Graziano, U. Ferrando, and G. Camussi CD133+ Renal Progenitor Cells Contribute to Tumor Angiogenesis Am. J. Pathol., December 1, 2006; 169(6): 2223 - 2235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Perk, I. Gil-Bazo, Y. Chin, P. de Candia, J. J.S. Chen, Y. Zhao, S. Chao, W. Cheong, Y. Ke, H. Al-Ahmadie, et al. Reassessment of Id1 Protein Expression in Human Mammary, Prostate, and Bladder Cancers Using a Monospecific Rabbit Monoclonal Anti-Id1 Antibody. Cancer Res., November 15, 2006; 66(22): 10870 - 10877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. O. Sakariassen, L. Prestegarden, J. Wang, K.-O. Skaftnesmo, R. Mahesparan, C. Molthoff, P. Sminia, E. Sundlisaeter, A. Misra, B. B. Tysnes, et al. Angiogenesis-independent tumor growth mediated by stem-like cancer cells PNAS, October 31, 2006; 103(44): 16466 - 16471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. V. Litvinov, D. J. Vander Griend, Y. Xu, L. Antony, S. L. Dalrymple, and J. T. Isaacs Low-Calcium Serum-Free Defined Medium Selects for Growth of Normal Prostatic Epithelial Stem Cells. Cancer Res., September 1, 2006; 66(17): 8598 - 8607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Hall, J. Dai, K. L. van Golen, E. T. Keller, and M. W. Long Type I Collagen Receptor ({alpha}2{beta}1) Signaling Promotes the Growth of Human Prostate Cancer Cells within the Bone. Cancer Res., September 1, 2006; 66(17): 8648 - 8654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mehra, M. Penning, J. Maas, L. V. Beerepoot, N. van Daal, C. H. van Gils, R. H. Giles, and E. E. Voest Progenitor Marker CD133 mRNA Is Elevated in Peripheral Blood of Cancer Patients with Bone Metastases. Clin. Cancer Res., August 15, 2006; 12(16): 4859 - 4866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. Hezel, A. C. Kimmelman, B. Z. Stanger, N. Bardeesy, and R. A. DePinho Genetics and biology of pancreatic ductal adenocarcinoma. Genes & Dev., May 15, 2006; 20(10): 1218 - 1249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Strewler The Stem Cell Niche and Bone Metastasis IBMS BoneKEy, May 1, 2006; 3(5): 19 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Pienta and D. Bradley Mechanisms underlying the development of androgen-independent prostate cancer. Clin. Cancer Res., March 15, 2006; 12(6): 1665 - 1671. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
), dashed line; PE605 (
), solid line], one poorly differentiated Gleason 9 (PE434 (
), dashed line; PE563 (
), solid line], and one benign prostate [PE352 (
), solid line].
