bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4212: p53 null spindloid murine mammary tumors show features associated with human claudin-low tumors and enrichment for cancer stem cells
Authors: Herschkowitz Jason I. , Zhang Mei , Zhaow Wei , Murrow George W. , Edwards David , Knezevic Jana , Greene Stephanie B. , Medina Daniel , Perou Charles M. , Rosen Jeffrey M. 
Published: February 2011

Abstract
The claudin-low subtype is a recently identified new and rare molecular subtype of human breast cancer which we hypothesize may be enriched for cancer stem cells or tumor-initiating cells (TIC). These tumors express low levels of tight and adherens junction genes including claudin 3 and E-cadherin. Claudin-low tumors also often highly express markers associated with epithelial-mesenchymal transition (EMT) including EMT inducers Snail, Twist, Zeb1, and Zeb2. These tumors are also enriched in recently published signatures derived from human TICs and a sorted population enriched for human mammary stem cells. Using comparative genomics, we discovered that there are mouse mammary tumors that have similar gene expression characteristics as claudin-low human tumors and are also enriched in the human TIC signature. Tumors in this group were rare tumors which came from a number of distinct mouse models including the p53 null transplant model. We have now collected over forty more tumors from the p53 null model, a phenotypically heterogeneous tumor model, in order to identify tumors of different molecular subtypes including claudin-low/spindloid tumors that can be transplanted and expanded in vivo. Here we present a molecular characterization of the p53 null mammary tumor bank as compared to other mouse models and human breast tumor subtypes. Similar to human tumors, the p53 null tumors fall into multiple molecular groups, a basal-like subtype, a luminal subtype, and a claudin-low subtype. Like human breast tumors, the p53 null claudin-low tumors show high expression of EMT inducers. They also show low to absent expression of both claudin 3 and E-cadherin by microarray as well as immunostaining. These groups also contain distinct genomic copy number changes as assessed by array comparative genomic hybridization. Finally, we show by limiting dilution transplantation, that p53 null claudin-low tumors are significantly enriched for TICs as compared to the more common adenocarcinomas arising in the same model. In conclusion, p53 null claudin-low/spindloid tumors show features of human claudin-low tumors and they are enriched for TICs, which has yet to be demonstrated experimentally for human claudin-low tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4212.
Abstract 4214: Stem cell antigen-1 (Sca1) modulates PI3K/PTEN signaling and mammary tumor cell survival
Authors: Upadhyay Geeta , Pollock Claire , Yin Yuzhi , Yuan Hongyan , Kopelovich Levi , Glazer Robert I. 
Published: February 2011

Abstract
Stem cell antigen-1 (Sca-1, Ly6A/E) represents two allelic forms of a GPI-anchored membrane protein that was first identified as a murine marker of bone marrow stem cells. Although Sca-1 is widely used to enrich for stem cells in many normal tissues, little is known about its function and associated signaling pathways in tumorigenesis. To explore this further, mammary carcinogenesis was induced in Sca-1+/EGFP mice that are heterozygous for Sca-1 and express GFP under the control of the Sca-1 locus. Induction of mammary tumorigenesis by progestin/DMBA treatment resulted in a marked increase of Sca-1 in the mammary gland at the initiation of tumorigenesis, as well as in the resulting tumors. To further investigate the function of Sca1, tumor cell line 34T was established from a primary adenocarcinoma, and sorted into Sca-1hi and Sca-1lo populations. These results revealed that Sca-1 expression related inversely with proliferation, as well as PTEN, PDK1, pT308Akt and pERK1/2 expression. Furthermore, reduction of Sca-1 in 34T cells by lentivirus-mediated RNAi reversed the proliferative, PTEN and kinase phenotype, and resulted in loss of their ability to proliferate as spheroid clusters in cell culture. Isografts of 34T/Sca-1hi and 34T/Sca-1lo cells in syngeneic mice indicated that Sca-1 was essential for tumorigenicity. These results provide evidence that Sca-1 confers a proliferative and survival advantage to mammary tumor cells, and demonstrates for the first time that Sca1 is associated with modulation of the PTEN/PDK1/Akt axis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4214.
Abstract 4217: Contrasting mouse mammary cancer stem cells before and after EMT
Authors: Maurer Jochen , Hebbard Lionel , Castro David J. , Altman Yoav , Terskikh Alexey , Oshima Robert G. 
Published: February 2011

Abstract
We isolated mouse mammary cancer stem cells from a Wnt1-driven tumor model of aggressive breast cancer. These tumorigenic progenitor cells show expression of marker of both luminal (keratin 8) and myoepithelial (keratin 14) cells, express CD24, CD29 and CD49f surface markers. The K8+, K14+ double positive cells can be greatly enriched from less than 5% of the tumor to greater than 60% of the cultured cells in a 3D-culture system under hypoxic conditions. Transplantation of these cultured cells generated tumors with the differentiated morphology of the tumor of origin from a few as a single cell. In a 2D culture setting under normoxic conditions, double positive cells generate single positive differentiated derivates. Serial transplantation of the tumor generated from the cultured cells resulted in increasing growth rate reflected by reduced generation time from 52 days to 21 days after four passages. The fast-growing tumors were strongly positive for vimentin, negative for K14 and few cells expressed K8. Analysis of the cells in 2D revealed a fibroblast-like growth pattern. When grown in 3D, the cells do not form spheroids but rather grow in an invasive pattern in Matrigel. This tumor line has undergone an epithelial to mesenchymal transition (EMT). These cells also generate tumors from single cell transplants but do not generate heterogeneous tumors.
In summary, we have succeeded in cultivating a mammary cancer stem cell, demonstrated its self renewal capacity and potential for differentiation both in vivo and in culture. Furthermore, we have isolated an EMT derivative that is tumorgenic but appears to have lost the potential for self limiting differentiation. This demonstrates that tumorigenic cells with severely restricted capacity for differentiation can be derived from a cancer stem cell. Potential therapies based on the potential of cancer stem cells to differentiate may need to be applied at very early stages of the development of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4217.
Abstract 4225: Expression of NANOG in a prostate cancer cell line increases CD24 expression and enhances cell invasion
Authors: Fowler Macie , Glass Jonathan , Yin Hong 
Published: February 2011

Abstract
The transcription factor NANOG is critical for the maintenance of embryonic stem cell properties including self-renewal and pluripotency. NANOG performs these functions by regulating the expression of genes required for the preservation of the stem cell phenotype. Introduction of NANOG and other embryonic stem cell genes has successfully established disease-specific induced pluripotent stem cells in several types of human cancers. Although the expression of NANOG has been documented in cancer cells, the function of NANOG in cancer has not been extensively investigated.
We hypothesized that NANOG plays a role in prostate cancer cell biology based on our observation of NANOG protein expression in prostate cancer cell lines. To test this hypothesis, we transduced the PC3 prostate cancer cell line with a lentivirus capable of directing the expression of NANOG. A stable cell line containing the NANOG expression cassette was established by selection with puromycin, and expression of NANOG protein was verified by Western blot analysis. Analysis of stem cell surface markers by flow cytometry in the PC3-NANOG cells and PC3 cells transduced with empty virus revealed an increase in the percentage of CD24 positive cells in the PC3-NANOG sample as compared with the control. In addition, the density of CD24 per cell appeared to increase. This increase in CD24 expression was confirmed by Western blot analysis.
In multiple cancers expression of CD24, a mucin-like adhesion protein, correlates with invasion and metastatic potential. Therefore, we conducted an invasion assay to assess the ability of PC3-NANOG cells to invade through a matrix assaying invasion by migration of cells from one chamber of a bicameral chamber through a porous membrane. The results showed that PC3-NANOG cells exhibited a 30-40% increase in invasion as compared to the control cells. (p&lt;0.001). These results suggest that expression of NANOG in a prostate cancer cell line contributes to increased invasive capacity, possibly through enhanced expression of CD24. Therefore, NANOG could be a potential mediator of prostate cancer cell invasion and maneuvers to decrease NANOG expression could be a new therapeutic target for treatment of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4225.
Abstract 4228: A functional role of OCT4 for prostate tumor initiation
Authors: Linn Douglas E. , Yang Xi , Sun Feng , Xie Yingqiu , Chumsri Saranya , Burger Angelika , Qiu Yun 
Published: February 2011

Abstract
We have established several drug resistant prostate cancer cell lines by long term culturing hormone refractory CWR-R1 cells in medium containing chemotherapeutic drugs. These cells displayed a significant increase in side-population cells due to overexpression of drug efflux pumps including ABCG2/BCRP and MDR1. To further characterize drug resistant CWR-R1 prostate cancer cell lines, we performed microarray analysis on two drug resistant cell lines in comparison with the drug sensitive parental line. Our Ingenuity pathway analysis suggested that OCT4/POU5F1, the key transcription factor for regulating pluripotency in embryonic stem cells, was upregulated in the drug-resistant lines compared to the parental cells, which was accompanied with transcriptional activation of a set of OCT4 known target genes. Upregulation of OCT4 in drug resistant cells was validated by RT-PCR and sequencing of PCR products as well as confirmed by western blot and specific shRNA knockdown. Analysis of the regulatory region of OCT4 gene revealed that drug-resistant cell lines had reduced methylation compared to the parental line. Furthermore, these drug resistant cells exhibited a significant increase in transformation activity in vitro and tumorigenicity in vivo.
Subcutaneous inoculation of as few as ten drug-resistant cells could initiate tumor formation in SCID mice, whereas no detectable tumors were observed from the parental line under similar conditions. Our data suggest that these drug resistant cells may be enriched for tumor initiating cells. Knock-down OCT4 expression in drug-resistant cells by the specific shRNA resulted in a considerable decrease in growth both in vitro and in vivo. Our data suggest that OCT4 may play an essential role in promoting tumor initiation of prostate cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4228.
Abstract 4229: Wound repair promotes ovarian cancer stem cell self-renewal
Authors: Chefetz-Menaker Ilana , Lebowitz Noah , Aldo Paolomi , Alvero Ayesha , Holmberg Jennie , Mor Gil 
Published: February 2011

Abstract
Background: In normal tissues following injury, there is an expansion of tissue specific stem cells prior to their differentiation to initiate injury repair. Once the tissue is repaired, the stem cells return to a quiescent state. Tumor tissue, might follow similar characteristics as in normal tissues, but the control of the expansion process may be significantly altered. Recently, ovarian cancer stem cells (ovCSC) were isolated from ovarian cancer tissue and ascites using CD44/CK18 as markers. We hypothesize that these cells play a critical role in tumor repair and renewal. To test this hypothesis, we used an in vitro wound/healing system.
Methods: Cells were plated in an Essen ImageLock plate and wounds were made using an Essen WoundMaker. This sytem allows the generation of consistent wound locations and widths and precise imaging of the wound area. The healing process is monitored using an insitu imaging system (IncuCyte, Essen Instruments, NH) that records and quantifies the repair process in real time. Levels of cancer stem cell markers, CD44, Oct-4, and β-catenin were determined by Western blot analysis or Real Time PCR. Levels of cytokines and chemokines were determined using Luminex Technology.
Results: Initially we tested whether an in vitro wound/healing system can be used as a renewal model. Interestingly, ovCSCs showed a well coordinated and organized response to the wound. First, the cells created a “straight line” to replace the irregular edge of the wound. Afterwards, the cells proliferated towards the wound, repairing the wound until confluence was reached. Analysis of cancer stem cell markers by Western blot revealed that the cells which repaired the wound maintained CD44, CK18, Oct4, and β-catenin, previously shown as ovCSC markers. Additionally, the process of repair was characterized by significant and differential up-regulation in IL-6, GRO-α, and MCP-1 expression and secretion. Interestingly, the CD44 expression was increased in wounded wells when compared to control. Moreover, using specific primers for CD44 variant isoforms we found that wound healing promotes expression of different CD44 forms.
Conclusions: In this study we demonstrate ovCSCs have the capacity to repair an in vitro wound and that this process is accompanied by increased CD44 expression and cytokine secretion. This increased capacity of self renewal can lead to the accumulation of a large pool of progenitor cells, which has the potential to individually spread to other areas of the body as metastatic cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4229.
Abstract 424: Invasion and metastasis of human colon cancer cells is prevented by aldose reductase inhibition
Authors: Srivastava Satish K. , Tammali Ravinder , Rychahou Piotr G. , Evers Mark B. , Awasthi Sanjay , Ramana Kota V. 
Published: February 2011

Abstract
Worldwide colorectal cancer (CRC) is the third most common cause of cancer and is the second leading cause of cancer deaths in the USA. Although therapeutic options for patients with CRC have increased substantially, including earlier diagnosis, improved surgery as well as chemo- and radiation therapies, ∼61% of patients have metastatic disease and of these, 90% die within 5 years of diagnosis. Hence better therapeutic interventions to manage the metastatic process in CRC patients are mandatory. We have recently shown that inhibition of aldose reductase (AR), an enzyme that catalyzes reduction of lipid aldehydes and their glutathione conjugates, prevents human colon cancer cell growth in culture as well as in nude mice xenografts by inhibiting the NF-kB-dependent activation of inflammatory and carcinogenic markers. We have now investigated the effect of AR inhibition in metastatic spread of human CRC cells in nude mice and the molecular mechanisms by which AR inhibition prevents colon cancer cell invasion, migration, adhesion and metastasis. Our results indicate that AR inhibition prevents growth factors-induced migration and invasion of HT-29 CRC cells in a dose-dependent manner. AR inhibition also significantly inhibited adhesion of CRC cells to endothelial cells and inhibited the expression of ICAM-1, VCAM-1 and VE-cadherin. Further, we injected KM20 cells, transfected with a plasmid containing green fluorescent protein (GFP), into the spleen of athymic nude mice to establish liver metastases. The mice were treated with AR inhibitor or siRNA for 30 days. Our results indicate that AR inhibition or ablation prevents in vivo invasion and metastasis of CRC cells by reducing levels of AR, MMP2, cyclin D1, and CD34 and suppresses the activation of NF-kB. Since AR inhibitor fidarestat aggressively prevents human tumor growth and metastasis in nude mice and cellular models, and has already undergone phase-iii clinical studies for diabetic neuropathy, it is an excellent candidate for clinical application in preventing colon cancer tumorigenesis and metastasis.
Funding Support: NIH/NCI CA129383 (SKS).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 424.
Abstract 4242: TRP53 DELETION INDUCES PROLONGED SURVIVAL OF BIPOTENT LIVER STEM CELLS AND THE EVOLUTION OF BI-DIFFERENTIATED HCC/CC
Authors: Lechel André , Katz Sarah-Fee , Begus-Nahrmann Yvonne , Hartmann Daniel , Schirmacher Peter , Rudolph K. Lenhard 
Published: February 2011

Abstract
Background:
Defects in the p53-signaling checkpoint have been described in 30-60% of human hepatocellular carcinoma (HCC) and are associated with less differentiated tumors and poor prognosis. The contribution of p53 deletion by itself to hepatocarcinogenesis is not known. Furthermore it is not clear, if liver stem cells play a role in the onset of liver tumor formation.
Methods:
We generated mice with liver specific TRP53 deletion (TRP53−/−) by crossing conditional TRP53 KO mice with AlfpCRE transgenic mice (CRE expression under the albumin-alphafetoprotein-enhancer-promoter). In vitro cultures were established from the developing liver tumors and analyzed for potential tumor stem cells using xenotransplantation. Endogenous liver stem/progenitor cells were analysed using FACS purification and in vitro culturing of purified liver stem cells (CD13+CD133+CD49f+).
Results:
Mice with liver specific TRP53 deletion developed liver tumors with a mixed differentiation (hepatocellular and cholangiocellular carcinoma). Purification and xenotransplantation of subpopulations of tumor cells from primary tumor cell cultures (using following surface marker: CD13, CD90, CD133, or cKit) revealed no differences in tumor forming capacity in NMRI nu/nu mice. Moreover, tumor formation was seen after xenotransplantation of very small tumor cell numbers (2-cells) indicating that the tumors have an inherent high tumor forming capacity.
An analysis of the colony formation capacity of endogenous liver stem/progenitor cells revealed a prolonged survival of bipotent liver stem cells in aged TRP53−/− mice compared to TRP53+/− or TRP53+/+ mice. The last two groups showed a complete loss of bipotent liver stem cells by 8 month of age, whereas bipotent liver stem cells were detected with a frequency of 0,4% in liver of 8-10 month old TRP53−/− mice.
Conclusion:
This study provides the first experimental evidence that TRP53 deletion leads to a prolonged survival of bipotent liver stem cells and the formation of bi-differentiated liver tumors. These data indicate that the p53-dependent tumor suppressor functions include the restriction of proliferation and survival of bipotent stem cells in the liver.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4242.
Abstract 4247: MicroRNA profile of the human colonic crypt base region is predictive of colon cancer
Authors: Haghighat Sepehr Sedigh , Viswanathan Vignesh , Opdenaker Lynn , Gonye Greg , Zhang Tao , Boman Bruce M. , Petrelli Nicholas J. 
Published: February 2011

Abstract
Dysregulation of crypt cell proliferation and differentiation has been implicated in the development of colorectal cancer (CRC). It is believed that human colonic crypt renewal involves programmed cellular proliferation initiated by a few (6-8) stem cells residing at or near the bottom of the crypt, and that stem cell (SC) overpopulation may be the key to CRC initiation. As part of our investigation of regulatory factors involved in the stem cell origin of CRC, we investigated the role that microRNAs (miRNAs) might play in colon carcinogenesis. miRNAs are RNAs 20-24 nucleotides long that were recently shown to modulate many cellular signaling pathways through post-transcriptional regulation of messenger RNA (mRNA) levels and thus protein synthesis. Our previous microarray analysis (368 gene chip) showed increased expression of 37 miRNAs in CRCs compared to normal colonic epithelium. Here we further evaluated miRNA expression in CRC versus purified colonic epithelium by quantitative PCR (QPCR). Total RNA was immediately isolated from tissue by the TrizolTM method. RNA was transcribed into first-strand complementary DNA (cDNA) through reverse transcription (RT). cDNA was then amplified through QPCR. Statistical analysis and plots of expression data for miRNAs were done to find miRNA genes that are differentially expressed. We found, using QPCR, five miRNAs to be differentially expressed in CRCs versus normal colonic epithelium including mir-25 and mir-198. Profiling of purified colonic crypt subregions showed that a distinct signature involving 16 differentially expressed miRNAs characterizes the crypt bottom. This miRNA signature of the crypt bottom was found to be predictive of CRC. Out of the sixteen, three miRNAs (mir-206, mir- 7 and mir-25) were independently capable to distinguish colorectal tissue from normal colonic epithelia (p&lt;0.01). Because this subset of miRNAs is differentially expressed in the crypt bottom, where SC resides, they may be involved in regulating SC population dynamics and contribute to the SC origin of CRC. Further identification and characterization of miRNAs expressed specifically in SC and changes in their expression in CRCs will provide important information to help understand mechanisms of colon tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4247.