bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3105: Chromosome 18q encodes a chromosomal instability suppressor locus in colorectal cancer
Authors: Burrell Rebecca A. , McClelland Sarah E. , Endesfelder David , Rowan Andrew , Schenk Arne , Sheffer Michal , Shaikh Nadeem , Domingo Enric , Kschischo Maik , Domany Eytan , Downward Julian , Tomlinson Ian , Swanton Charles
Published: August 2012

Identifying molecular mechanisms initiating Chromosomal Instability (CIN) may lead to approaches to limit intratumour heterogeneity and treatment failure in cancer. Here we identify candidate CIN-suppressor genomic loci that are subject to copy number loss in CIN colorectal cancers (CRCs). Genes encoded within CIN-suppressor loci were characterized through an RNA interference screen for induction of chromosome segregation errors in mitosis, revealing 5 CIN-suppressor genes encoded on chromosome 18q. CIN-suppressor gene silencing in chromosomally stable cells generates structurally abnormal chromosomes, which are missegregated during mitosis. A chromosome segregation error spectrum characteristic of structurally abnormal chromosomes is also observed in CIN CRC cell lines. 18q loss occurs in the majority of aneuploid CRCs, and is associated with both structural and numerical instability in colorectal tumours, and with aneuploidy onset in a rare carcinoma-in-adenoma dataset. These data support a role for chromosome 18q in the maintenance of chromosomal structural integrity and mitotic fidelity, and suggest that 18q copy number loss may initiate CIN during CRC development.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3105. doi:1538-7445.AM2012-3105
Abstract 3106: Collagen-mediated chromatin remodeling promotes chemoresistance in pancreatic cancer
Authors: Dangi-Garimella Surabhi Y. , Munshi Hidayatullah G.
Published: August 2012

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related deaths in the US, is associated with a pronounced collagen-rich stromal reaction that has been shown to contribute to chemo-resistance. We have previously shown that PDAC cells grown in the collagen microenvironment are resistant to gemcitabine-induced proliferation- and checkpoint-arrest (Dangi-Garimella et al, Cancer Research 2011). The effects were mediated by ERK1/2-dependent expression of high mobility group A2 (HMGA2), a well-known chromatin remodeling protein. We have now found that relative to cells grown on tissue culture plastic, PDAC cells grown in 3D collagen display increased acetylation of lysines K9 and K27 on histone H3 along with a reduction in the levels of the heterochromatin binding protein HP1-α, suggesting that cells in collagen have a more open chromatin state. Decreasing HMGA2 expression or inhibiting ERK1/2 activity attenuates the effect of collagen on K9 and K27 acetylation. 3D collagen also promotes expression of the histone acetyl transferase (HAT) enzymes PCAF and GCN5 through increased HMGA2 expression and ERK1/2 activation. Additionally, human PDAC tumors display higher histone acetylation near fibrotic regions that also have increased HMGA2 expression. Finally, cells in 3D matrix demonstrate increased H2AX and a reduced tailing with the comet assay following gemcitabine treatment, suggesting that there is increased DNA repair associated with the more open chromatin state when cells are in the 3D collagen microenvironment. Downregulation of HATs along with inhibition of ERK1/2 phosphorylation attenuates gemcitabine-induced H2AX detected in 3D collagen. Overall, our results increase our understanding of how growth in 3D collagen contributes to chemo-resistance and identify potential therapeutic targets against this deadly cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3106. doi:1538-7445.AM2012-3106
Abstract 3111: Synthetic lethality in head and neck cancer
Authors: Lajud Shayanne A. , Yamashita Taku , Han Ziying , Zheng Jun , Mouchli Anas , Bezpalko Orysia , O'Malley Bert W. , Li Daqing
Published: August 2012

Current treatment for advanced stage head and neck squamous cell carcinoma (HNSCC) typically include both radiation and chemotherapy, which is associated with significant morbidity. Our main objective was to explore a novel adjuvant molecular therapy approach to minimize the chemoradiation-induced side effects and toxicities, while maintaining therapeutic anti-tumor effects in HNSCC through the mechanism of synthetic lethality that has been already exploited to a limited extent in clinical trials for breast cancer. It has been demonstrated that synthetic lethality is based on the roles of Poly(ADP-ribose)polymerase-1 (PARP-1) in DNA single-stranded break (SSB) repair, and BRCA-1 and -2 in double-stranded break (DSB) repair. By simply inhibiting PARP-1 in tumor cells carrying a mutation in the Brca genes, one would expect complete tumor regression. The MRN complex (Mre11, Rad50, and Nbs-1) is well recognized as a key sensor of DSBs and acts by recruiting and activating DNA damage response proteins. These concepts led us to investigate the concept of introducing a mutation to the MRN complex, in combination with PARP-1 inhibition, thereby creating “dual hits” that would result in synthetic lethality within tumors expressing wild-type Brca genes such as HNSCC. Human HNSCC tumor cell lines and a mouse model with human HNSCC were used in the study. Wild-type MRN and PARP expressions were detected in these tumor cells. In vitro and in vivo studies were performed to evaluate synthetic lethality effects after combining PARP-1 inhibition with adenovirus-mediated Nbs-1 (Ad-Nbs-1) gene transfer treatment, which we had previously shown to impair MRN expression. Telomere length was measured to investigate the potential mechanism of synthetic lethality. Our study demonstrates that significant synthetic lethality was found with combined PARP-1 inhibition and Ad-Nbs-1 treatment in both in vitro and in vivo experiments; it also suggests that the telomere maintenance may play an important role in synthetic lethality. In conclusion, we propose an important novel mechanism responsible for the synthetic lethality of PARP-1 inhibitors and MRN disruption based on their roles on telomere maintenance. Our findings emphasize the potential benefits of our therapeutic approach and deserve further investigation to help obviate the toxicities associated with existing treatment regimens for HNSCC patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3111. doi:1538-7445.AM2012-3111
Abstract 3114: Mutational inactivation of STAG2 causes aneuploidy in human cancer
Authors: Solomon David , Kim Taeyon , Diaz-Martinez Laura , Fair Joshlean , Elkahloun Abdel , Harris Brent , Toretsky Jeffrey , Rosenberg Steven , Shukla Neerav , Ladanyi Marc , Samuels Yardena , James C. David , Yu Hongtao , Kim Jung-Sik , Waldman Todd
Published: August 2012

One of the hallmarks of cancer is chromosomal instability, which leads to aneuploidy, translocations, loss of heterozygosity, and other chromosomal aberrations. Chromosomal instability is an early event in cancer pathogenesis and is thought to help generate the large number of genetic lesions required for a cell to undergo malignant transformation. It has been hypothesized that this instability is due to inactivating mutations in genes that control the mitotic checkpoint and chromosome segregation. However, in the vast majority of human tumors the molecular basis of chromosomal instability and the aneuploidy it produces remains unknown. We have recently identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors (Science 333:1039, 2011). A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer. These findings and additional unpublished observations regarding the role of STAG2 inactivation in aneuploidy will be presented.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3114. doi:1538-7445.AM2012-3114
Abstract 3177: Transcriptome sequencing identifies oncogenic microRNA signatures that interact with NF-kappaB, TP53 and Notch signaling in head and neck squamous cell carcinoma
Authors: Saleh Anthony D. , Si Han , Lu Hai , Yang Xinping Yang , Chen Zhong , Waes Carter Van , Coupar Jamie
Published: August 2012

MicroRNA dysregulation has been shown to be nearly universal in cancer biology, driving oncogenic signaling networks. However, microRNA mediated global regulatory mechanisms underlying malignant phenotypes of head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we have performed genome-wide small RNA sequencing on a panel of nine HNSCC cell lines and three normal primary oral keratinocyte cell lines, as well as matched primary tumor and normal tissues using the SOLiD parallel sequencing platform. A panel of microRNAs with altered expression was identified, including several novel oncogenic microRNAs which are upregulated in parallel with altered activation of NF-kB c-REL, TP53 family members ΔNp63α and TAp73, and involved in the down-modulation of p53 and Notch1, two genes most often mutated or inactivated in HNSCC. To examine the hypothesis that these microRNAs could potentially be regulated by NF-κB and p53 pathways, NF-κB inducer TNF-α was used to treat an HNSCC cell line overexpressing mtTP53, ΔNp63α and TAp73. Genome-wide small RNA sequencing revealed significant changes in microRNA expression modulated by TNF-α that overlaps with the panel of constitutively dysregulated microRNAs in HNSCC. Furthermore, genome-wide ChIP-sequencing revealed that TNF-α modulated DNA binding activities of c-REL, ΔNp63α and TAp73 aligned within the regulatory regions of several differentially expressed microRNAs. Modulation of these microRNAs with anti-miR repression reduced proliferation and motility in HNSCC cell lines, which confirmed the oncogenic activity of the microRNAs and their potential for therapeutic targeting.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3177. doi:1538-7445.AM2012-3177
Abstract 319: The mucin MUC16 protects ovarian cancer cells from innate immune responses
Authors: Felder Mildred , Connor Joseph , Rakhmilevich Alexander , Qu Xiaoyi , Kapur Arvinder , Patankar Manish S.
Published: August 2012

Epithelial ovarian cancer cells overexpress the mucin MUC16. The estimated molecular weight of this membrane spanning mucin is ∼5 million Da. CA125, a diagnostic marker used to monitor regression and recurrence of ovarian cancer in patients undergoing treatment for this disease, is a repeating peptide epitope present in MUC16. Recent studies have indicated that MUC16 facilitates metastasis of ovarian cancer cells and likely also plays a pro-oncogenic role. We have demonstrated that MUC16 protects the ovarian cancer cells from natural killer (NK) cell-mediated cytotoxicity. The large molecular weight allows the mucin to act as a barrier around the cancer cells and prevent the formation of activating immune synapses between NK cells and ovarian cancer cells. In addition, MUC16 also inhibits NK cell responses by interacting with the inhibitory receptor Siglec-9. Here, we extend these initial studies to demonstrate that knockdown of MUC16 impairs ovarian cancer cells from forming tumors in SCID mice. Cytotoxicity experiments using splenocytes from SCID mice proved that the residual biologically active macrophages and NK cells from SCID mice are able to more effectively lyse the MUC16 knockdown ovarian cancer cells as compared to control cells expressing this mucin. The higher susceptibility of the MUC16 knockdown cells to immune cell mediated lysis was also observed when assays were conducted with murine effectors that were previously stimulated with anti-CD40 antibody. In addition, our data also demonstrates that humanized anti-EpCAM antibody is unable to overcome the immunesuppression mediated by MUC16. Stimulation of the immune cells with the cytokine huKS-IL2, an immunotherapeutic agent used in ovarian cancer clinical trials, also does not circumvent the immunosuppressive effects of MUC16. The data we have obtained indicates that ovarian cancer cells specifically express MUC16 to protect themselves from immune attack. Modulation of MUC16 expression may therefore serve as a useful strategy to control the progression of ovarian cancer via immunologic therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 319. doi:1538-7445.AM2012-319
Abstract 3267: Mammalian target of rapamycin (mTOR) signaling proteins are highly expressed in mamamry tumors of MMTV-TGF-β mice
Authors: Dogan Soner , Cleary Margot P.
Published: August 2012

Although the roles of many signaling pathways have been investigated to determine their potential role mammary tumor (MT) development the exact molecular mechanisms of mammary tumorigenesis are still not clear. One pathway of interest with respect to cancer development is mTOR signaling which is implicated in cell growth, transcription, translation, migration, differentiation, and survival. In the present study the expression levels of proteins associated with mTOR signaling pathway in MTs and in normal mammary tissues and fat pads were determined in MMTV-TGF-β transgenic mice that develop hormone responsive MTs as they age. Mice were enrolled at 10 wks of age and were ad-libitum-fed AIN-93M diet until 73/74 wks of age. At this time MTs were removed as well as mammary tissue samples from the same location where MT initially grow. Samples were analyzed histopathologically to confirm either MT or normal mammary tissue and mice assigned to MT-positive or MT-negative groups (n=6-8 per group). Protein expression levels were then determined in MT, mammary tissue and as well as mammary fat pads (MFP). Serum insulin, IL-6 and TNF-α levels were also measured. MT- positive mice had 40% higher serum insulin level compared to MT- negative mice. In addition, serum IL-6 levels were 100% higher in MT- positive compared to the MT-negative group. Serum TNFα levels were similar in both groups. Expression levels of mTOR, p70S6K, p4EBP1, and HIF-1 proteins were significantly higher in MT of the MT-positive group compared to the corresponding tissue of MT-negative group, 64%, 106%, 129%, and 43%, respectively. On the other hand, IGF-I receptor (IGF-IR) expression level was significantly lower by 43% in the MT- positive group compared to the MT-negative group. The expression levels of p70S6K, p4EBP1, and HIF-1 proteins were similar in MFP tissues in both groups while mTOR level was lower in MFP taken from MT-positive compared to MT-negative mice. But, IGF-IR level was significantly higher, 187%, in MFP taken from the MT-positive group compared to the MT-negative group. These findings demonstrate that expression levels of the proteins involve in mTOR signaling pathway are higher in MTs compared to normal mammary tissue obtained from the site of MT origin. This supports the potential role of mTOR signaling proteins in breast cancer development and provides targets for cancer prevention. (Support CA101858, The Breast Cancer Research Foundation and The Hormel Foundation).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3267. doi:1538-7445.AM2012-3267
Abstract 3268: Histological and biological effects of substituted quinolines (gap junction enhancers) in a spontaneous mammary tumor model
Authors: Shishido Stephanie N. , Nguyen Thu Annelise , Delahaye Adelaide
Published: August 2012

Effective use of antineoplastic drugs depends on the ability to balance the killing of tumor cells against the inherent toxicity to the host. Antineoplastic agents that act primarily on rapidly dividing and growing cells produce multiple side effects and are dose limiting. In recent years, there has been the development of biologic response modifiers aimed at enhancing innate anti-tumor defense mechanisms. Previous publications showed that substituted quinolines possess potent inhibitory activities against breast cancer cells through the enhancement of gap junction intercellular communication. These drugs decrease 71% of xenograft breast tumors in nude mice. The objective of this project is to evaluate the effect of substituted quinolines in a spontaneous mouse mammary tumor model (PyVT). PyVT mice were used at three different stages (pre, early and late) to characterize histological and biological changes in the treated animals compared to controls. Substituted quinolines cause a decrease of tumor growth rate by 112%, 77%, and 57% in the pre, early, and late stages of tumor development, respectively. Treatment during the pre and early stages of tumor formation also resulted in a decrease in the total number of tumors. Western blot analysis of the pre stage tumors show that the gap junction protein connexin 43 is more expressed in treated animals compared to control and the contrary for connexin 46. In the early and late stages, connexin 43 is expressed less in treated mice than controls, and vice versa for connexin 46. The expression of these connexins in control tissue suggests that this is due to an overall increase in connexin 43 and a decrease in connexin 46 during tumor development and metastasis. Histology of vital organs showed no significant alteration in treated animals compared to controls. These findings provide evidence that substituted quinolines cause a significant tumor reduction in a spontaneous mammary tumor model with no obvious adverse effects.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3268. doi:1538-7445.AM2012-3268
Abstract 327: Properties associated with cancer progression in primary clonal epithelial and mesenchymal-like murine mammary tumor cells
Authors: Palen Katie A. , Johnson Bryon D. , Gershan Jill A.
Published: August 2012

The majority of cancer patients die from tumor relapse. Consequently, characteristics of tumor cells that may contribute to aggressive cancer progression are under intense investigation. Tumors are composed of heterogeneous populations of cells that express a continuum of epithelial and mesenchymal markers. There is mounting evidence that mesenchymal tumor cells acquire invasive features and are refractory to conventional treatment, but in order to decipher the contribution of both epithelial and mesenchymal-like tumor cells to disease relapse we must understand the cellular and molecular properties of each cell type. Using a combination of different culture conditions and cell sorting strategies, we cloned epithelial and mesenchymal-like tumor cells that were derived from FVB Tg MMTV/Neu spontaneous mammary tumors. The availability of these clonal primary cell lines provides an unique opportunity to compare tumor cell properties that may contribute to aggressive disease such as proliferation, resistance to apoptosis, tumorigenicity, invasiveness, expression of growth factor and cytokine receptors, inflammatory cytokine secretion, immunogenicity, and expression or down-regulation of immune-modulatory molecules. Some of our preliminary data has revealed that (1) Epithelial cells are more proliferative in vitro, and cell proliferation was reduced upon exposure to the tyrosine kinase inhibitor, TKI-258. TKI-258 did not significantly decrease the proliferation of mesenchymal-like tumor cells, (2) A population of epithelial-enriched cells was more tumorigenic as compared to mesenchymal-like-enriched cells when administered to an immune competent syngeneic host, (3) Epithelial cells express greater Neu transgene, IL-6 and TNF-α transcripts than mesenchymal-like cells, and (4) When low passage clonal epithelial and mesenchymal-like cells were used as a whole cell tumor vaccine in FVB wild-type mice there was an increase in CD8 T cell activation as compared to that elicited by administration of a non-clonal high passage tumor cell line. We are continuing to explore molecular and functional differences between the clonal epithelial, clonal mesenchymal and the non-clonal tumor cell line cells. Characterization of epithelial and mesenchymal-like tumor cells represents an initial step in deciphering how tumor cells contribute to aggressive cancer progression and will offer insight into how epithelial and mesenchymal-like tumor cells respond to therapeutic interventions. The ultimate goal will be to tailor anticancer therapy toward eradicating the unique type of tumor cells that populate patient tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 327. doi:1538-7445.AM2012-327
Abstract 3279: Potential beneficial effects of the BRCA1 mutation carrier state on bone strength
Authors: Liu Ying , Yen Hai-Yun , Gabet Yankel , Wu Nancy , Pike Malcolm C. , Frenkel Baruch , Maxson Robert , Dubeau Louis
Published: August 2012

We previously suggested, based on observations in a mouse model in which we conditionally inactivated Brca1 in ovarian granulosa cells, that mutant mice are exposed to higher estradiol levels and also have prolonged estradiol exposure unopposed by progesterone due to an increase in the proestrus phase of their estrus cycle relative to metestrus. We sought to examine the biological significance of increased hormonal stimulation in homozygous Brca1 conditional knockout mice and to test the hypothesis that the effect is also present in mice with a heterozygous mutation such as present in human BRCA1 mutation carriers. We use endometrial cellular proliferation as an indicator for short-term effects of a Brca1mutation. Long-term effects were examined by measurements of long bone parameters using micro-computed tomography. The relative effects of heterozygous versus homozygous Brca1 mutations were evaluated by measuring the expression of enzymes involved in estradiol biosynthesis in granulosa cells. Mutant mice synchronized in the proestrus phase of their estrus cycle showed an increase in endometrial stromal cell proliferation in (P = .01). Mutant mice also showed an increase in trabecular bone density (P = .01) and femoral length (P = .02). Protein expression of aromatase and Hsd3B was higher in granulosa cells of mice carrying a heterozygous mutation in their ovarian granulosa cells compared to wild type littermates (P = .005 and .006 respectively). Our results provide a potential explanation for epidemiological observations to the effect that height is associated with increased risk for breast and ovarian cancer. The results also suggest that BRCA1 mutations, while associated with increased cancer risk, may also have some inherent advantages such as increased bone strength that may have contributed to the maintenance of mutated BRCA1 alleles in the human gene pool. Heterozygous Brca1 mutations such as present in human BRCA1 mutation carriers are not silent.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3279. doi:1538-7445.AM2012-3279
Abstract 3292: A genetically engineered mouse model for high grade serous “ovarian” carcinoma arising in the fallopian tube
Authors: Perets Ruth , Muto Katherine W. , Bijron Jonathan G. , Kenneth Chin T. , Poole Barish B. , Crum Christopher P. , Dinulescu Daniela M. , Drapkin Ronny
Published: August 2012

Ovarian cancer is the most lethal gynecologic malignancy because the vast majority of cases are detected in late stage, a finding that has thwarted attempts to understand the pathogenesis and cell-of-origin of this disease. The traditional view of epithelial ovarian pathogenesis asserts that all tumor subtypes share a common origin in the ovarian surface epithelium (OSE). There is robust data to support the OSE as the site of origin for many ovarian tumors, including low-grade carcinomas and borderline tumors. However, the pathogenesis of high-grade serous ovarian carcinoma, the most common type of ovarian cancer, continued to defy explanation by the OSE model. More recent studies suggested that the fallopian tube epithelium (FTE), rather than the OSE, may be the site-of-origin for a majority of pelvic serous carcinomas (PSC, defined as ovarian, peritoneal and tubal high grade serous carcinomas). We show here that the FTE can be site of origin for PSC by genetically engineering a mouse model that specifically targets the FT secretory cell with defined genetic alterations that are characteristic of human PSC. These mice develop tubal intraepithelial serous carcinomas, a precursor to PSC, that are morphologically and immunophenotypically similar to the lesions described in human patients. Furthermore, these intraepithelial lesions progress to widespread peritoneal disease that recapitulates the presentation of high-grade PSC in women. The tumors express common serous markers such as P53, αH2A.X, PAX8 and CA-125. Taken together our model is the first fully genetically engineered mouse model that truly recapitulates human serous carcinoma pathogenesis. Our model serves as proof-of-concept that the FTE can be site-of-origin to PSC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3292. doi:1538-7445.AM2012-3292
Abstract 3293: p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans
Authors: Wild Peter J. , Ikenberg Kristian , Fuchs Thomas , Georgiev Strahil , Noske Aurelia , Roessle Matthias , Caduff Rosmarie , Dellas Athanassios , Fink Daniel , Moch Holger , Krek Wilhelm , Frew Ian
Published: August 2012

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II carcinoma subtypes. The PI3K-Akt-mTOR signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, immunohistochemical analyses of 521 human endometrial carcinomas identified frequent mTOR pathway activation in type I as well as type II endometrial carcinoma subtypes and mTOR pathway activation and p53 expression each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the PI3K-mTOR pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and PI3K-mTOR pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3293. doi:1538-7445.AM2012-3293
Abstract 3314: Phenotypic plasticity in glioma stem cells mediated by NFκB signaling
Authors: Bhat Krishna P. L. , Vaillant Brian , Balasubramainyan Veerakumar , Ezhilarasan Ravesanker , Hollingsworth Faith , James Johanna , Wani Kahlida , Goodman Lindsey , Sulman Erik , Colman Howard , Aldape Kenneth
Published: August 2012

Here we report the identification of two major subtypes of glioma stem cells (GSCs) that closely mirror previously described glioblastoma (GBM) groups, namely proneural (PN) and mesenchymal (MES), based on gene expression patterns. Using flow cytometry, we found that PN GSCs express both CD15/SSEA1, a marker for neural stem cells, as well as CD44, a MES marker. In contrast MES GSCs were CD15low/CD44high. MES GSCs and CD44high subpopulations in PN GSCs showed increased expression of transcription factors previously reported to induce the MES phenotype (STAT3, C/EBP-α, and TAZ), and were -resistant to α-irradiation. By distilling cytokines that can induce MES differentiation, we found that TNF-α found in patient-derived microglial conditioned media or conditioned media from MES GSCs caused a PN-to-MES transition through activation of NFκB resulting in radio-resistance. We found that NFκB mediates MES transition indirectly by inducing the transcriptional circuitry of STAT3, C/EBP-α, and TAZ. Blockade of NFκB activation using minocycline abrogated the MES phenotype (both induced and constitutive), reduced tumor growth, and rendered GSCs radio-sensitive. Taken together, our findings reveal that phenotypic and surface marker plasticity is common in GSCs, and that the NFκB driven PN-to-MES transition provides an escape mechanism for GSCs to evade cytotoxic treatment. Based on our studies, we propose that minocycline, a commonly used antibiotic, could target GSCs and should be further evaluated in preclinical studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3314. doi:1538-7445.AM2012-3314
Abstract 3318: Phenotypic heterogeneity and instability of tumor-initiating cells in high-grade serous cancer
Authors: Stewart Jocelyn M. , Shaw Patricia A. , Bernardini Marcus Q. , Ailles Laurie E. , Neel Benjamin G.
Published: August 2012

Serous ovarian cancer (SOC) is the leading cause of morbidity/mortality from gynecologic malignancy. Current therapies significantly increase survival, yet 70-90% of SOC patients recur within five years and die of their disease. The cancer stem cell (CSC) hypothesis holds that only some tumor cells have the potential to initiate and maintain tumors. Moreover, CSC might be resistant to many therapeutic agents that are effective against bulk tumor cells, which could contribute to treatment failure. We have established a large collection of primary human SOC samples and developed a robust, quantitative assay for SOC tumor-initiating cells (TIC). Using this assay, we found that TIC from primary SOC can be identified based on their expression of the surface marker CD133. However, we also observed heterogeneity and instability of the TIC phenotype with disease progression. We examined whether instability in the TIC phenotype may be due to the acquisition of additional genetic alterations in the CD133- compared to the CD133+ fraction. Preliminary analysis suggests that most genetic alterations are common in both fractions; however, in 3/6 cases, additional genetic alterations were observed in the CD133- fraction, suggesting the emergence of CD133- TIC might be, at least in part, genetically driven. The mechanism of genetic instability is currently under investigation. In addition, we have used expression microarrays to examine differences between CD133+ and CD133- populations. We find that >1000 probes are differentially expressed in these two groups. We have identified several pathways with altered expression in TIC-enriched fractions. The biological role of these pathways in HG-SOC is under investigation. Our ability to identify and characterize TIC in this disease may facilitate development of new and more effective therapeutic strategies for ovarian cancer, thereby benefitting patients with this devastating disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3318. doi:1538-7445.AM2012-3318
Abstract 3321: Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial-mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma
Authors: Chien Chian-Shiu , Chiou Shih-Hwa
Published: August 2012

The high invasiveness and frequent recurrence of lung adenocarcinoma (LAC) are major reasons for treatment failures and poor prognoses. Alterations in microRNAs (miRNAs) expression have been shown in lung cancers. Recent reports have demonstrated that tumors contain a small subpopulation of cancer stem cells (CSCs) that possesses self-renewing capacity and is responsible for tumor malignancy including metastasis, relapse, and chemoradioresistance. However, a miRNAs-based therapeutic approach in LAC-associated CSCs (LAC-CSCs) is still blurred. Using miRNA/mRNA-microarray and Quantitative RT-PCR, we found that the expression of miR145 is negatively correlated with the levels of Oct4/Sox2/Fascin1 in LAC patient specimens, and an Oct4highSox2highFascin1highmiR145low phenotype predicted poor prognosis. We enriched LAC-CSCs by side population sorting or identification of CD133 markers and found that LAC-CSCs exhibited low miR145 and high Oct4/Sox2/Fascin1 expression, CSC-like properties, and chemoradioresistance. To clarify the role of miR145, we used a polyurethane-short branch-polyethylenimine (PU-PEI) as the vehicle to deliver miR145 into LAC-CSCs. PU-PEI-mediated miR145 delivery reduced CSC-like properties, and improved chemoradioresistance in LAC-CSCs by directly targeting Oct4/Sox2/Fascin1. Importantly, the repressive effect of miR145 on tumor metastasis was mediated by inhibiting the epithelial-mesenchymal transdifferentiation (EMT) and metastastic ability, partially by regulating Oct4/Sox2/Fascin1, Tcf4, and Wnt5a. Finally, in vivo study showed that PU-PEI-mediated miR145 delivery to xenograft tumors reduced tumor growth and metastasis, sensitized tumors to chemoradiotherapies, and prolonged the survival times of tumor-bearing mice. Our results demonstrated that miR145 acts as a switch regulating lung CSC-like and EMT properties, and provide insights into the clinical prospect of miR145-based therapies for malignant lung cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3321. doi:1538-7445.AM2012-3321
Abstract 3329: A let-7 signaling pathway targets metastatic genes enriched in tumor initiating cells
Authors: Frankenberger Casey A. , Yun Jieun , Eves Eva M. , Diehn Max , Minn Andy J. , Rosner Marsha R.
Published: August 2012

Stem-like “Tumor Initiating Cells” (TICs) have been isolated from a number of tumors including breast, and they are likely involved in all aspects of tumor biology including metastasis. Recent studies have established a link between epithelial stem-like properties and the epithelial-mesenchymal transition (EMT), a step that leads to invasion and metastasis. Identifying key signaling pathways that regulate both tumor initiating and metastatic events could enable more accurate prognosis and reveal important mediators of the process that could serve as novel therapeutic targets. Previous studies from our laboratory and others have shown that let-7 inhibits breast tumor initiation and metastasis. Previously, we have shown that BACH1, a transcription factor that is a direct target of let-7, promotes metastasis. Using gene expression arrays to quantify transcription in BACH1 depleted cells, we show that BACH1 regulates a number of downstream targets including Bone Metastasis Signature (BMS) genes. Utilizing an approach based on experimental and clinical validation, we identify genes implicated in both tumor initiation and metastasis. Gene set analysis confirmed that the BACH1 target genes significantly correlate to the metastatic pathway including BACH1, let-7 and BMS gene expression across a set of more than 1200 primary human tumors, and, in tumors selected for a basal phenotype, the expression levels of individual BACH1 target genes can significantly stratify metastasis free survival in patients. Using FACS to sort metastatic breast cancer cell lines, we see a significant increase in the transcription levels of BACH1 regulated genes when comparing TICs to non-tumor initiating cells. Additionally, in metastatic cell lines known to be enriched in TICs, BACH1 depletion reduces the population of cells expressing cell surface markers (CD44+CD24-/lowESA+) specific to a tumor initiating phenotype. And finally, gene set enrichment analysis indicates that BACH1 and the BACH1 target genes are enriched in human and mouse primary breast TICs relative to non-initiating tumor cells. Taken together, these results suggest that let-7 regulates a signaling cascade involving BACH1 and BACH1 target genes that promotes both tumor initiation and metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3329. doi:1538-7445.AM2012-3329
Abstract 3331: MicroRNAs regulate breast cancer stem cells and spontaneous metastases in orthotopic xenograft models
Authors: Liu Huiping , Bockhorn Jessica , Dalton Rachel , Nwachukwu Chika , Prat Aleix , Yee Kathy , Huang Simo , Swanson Kaitlin , Perou Charles M. , Olopade Olufunmilayo I. , Clarke Michael F. , Greene Geoffrey L.
Published: August 2012

To examine the role of microRNAs (miRNAs) in breast cancer progression, we profiled miRNA and gene expression in both clinical breast tumors and human-in-mouse breast tumor models, where breast cancer stem cells (BCSCs) contribute to spontaneous metastasis. CD44+ cells from both primary tumors and lung metastases were highly enriched for tumor initiating cells. Based on the miRNA profile analyses, we identified a limited number of miRNAs that are differentially expressed in metastatic triple-negative breast tumors and regulate BCSCs and tumor invasion in vitro. To facilitate miRNA functional studies in vivo, we also developed tumor imaging approaches by transducing BCSCs with optical reporter fusion genes (Luc2-eGFP or -tdTomato), which enabled both bioluminescence imaging (BLI) and FACS-based analysis and sorting. With non-invasive BLI approaches, as few as 10 cells of stably labeled BCSCs can be tracked in vivo. When optical reporters are expressed along with miRNA precursors or inhibitors, the effects of introduced miRNA candidates can be evaluated by selective imaging of labeled tumor cells, thereby eliminating the noise of unlabeled cells. Using this model system and imaging technology, we have screened and identified miRNAs that regulate BCSCs and metastatic CSCs (MCSCs) by targeting polycomb repressors (BMI1 and the PC2 components) and cytoskeleton genes (TWF1 and VIM). Clinical studies demonstrated that the expression of candidate miRNAs was associated with and regulated by GATA3, suggesting a transcriptional regulation of aberrantly expressed miRNAs in breast tumors. The GATA3-miRNA-target genes signaling pathway was also strongly associated with relapse-free survival of breast cancer patients, indicating the clinical importance of the miRNA-gene network in breast cancer. Supported in part by the University of Chicago Women's Board Fellowship (J.B.), NIH T90 Fellowship DK070103-05, DOD Postdoctoral Fellowship W81XWH-09-1-0331, and Chicago Fellows Program and CTSA UL1 RR024999 at The University of Chicago (H.L.), University of Chicago Cancer Research Center Pilot Research Fund, UCMC/Northshore Collaborative Research Award and the Virginia and D.K. Ludwig Fund (G.L.G and H.L). NIH R01 and Breast Cancer Research Foundation (M.F.C. and H.L.).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3331. doi:1538-7445.AM2012-3331
Abstract 3334: Antiangiogenic activity of honokiol through inhibition of vascular vessel formation in the mouse embryonic stem cell-derived endothelial cells
Authors: Kim Gi Dae , Bae Song Yi , Pyee Yuna , Shin Yoonho , Lee Min Ai , Song Jayoung , Chung Hwa Jin , Park Hyen Joo , Lee Sang Kook
Published: August 2012

Embryonic stem (ES) cells, which are characterized by pluripotency and self-renewal, have recently been highlighted in several aspects of drug discovery. In particular, the potential of ES cells to differentiate into specific-cell types make them an extremely useful tool in the evaluation of the biological activity of test compounds. In the present study, we employed mouse embryonic stem (mES) cell-derived embryoid bodies (EBs) to evaluate the antiangiogenic activity of natural compounds. Honokiol, a major neolignan derived from the bark of Magnolia obovata Thunberg (Magnoliaceae), was capable of inhibiting differentiation and vascular vessel formation in mES cell models. EBs were formed using hanging drop cultures. The induction of vascular formation was carried out on gelatin-coated plates in EGM-2 medium. Cell proliferation was measured by MTT assay. RT-PCR, immunocytochemistry, and Western blotting were used to measure differentiation of EBs into endothelial cells and vessel formation. The growth inhibition of honokiol in EB-derived endothelial cells was found that honokiol is more sensitive in the differentiated cells (on day 8) compared to the undifferentiated EB-derived endothelial cells (on day 1) with the IC50 values of 6.0 and 17.8 μM, respectively. Honokiol also dramatically decreased the expressions of an endothelial biomarker PECAM in the differentiated EB-derived endothelial cells (on day 11). Honokiol also suppressed the activation of p38 MAPK, Akt, ERK1/2 and SAPK/JNK in EB-derived endothelial cells. The antiangiogenic activity of honokiol is associated with the suppression of PECAM and the MAPK pathway in EB-derived endothelial cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3334. doi:1538-7445.AM2012-3334
Abstract 3337: TGF-β from niche fibroblasts increases the stemness cancer stem cell-like side population cells in gastric cancer
Authors: Hasegawa Tsuyoshi , Yashiro Masakazu , Morisaki Tamami , Aomatsu Naoki , Hirakawa Toshiki , Fukuoka Tatsunari , Matsuoka Junko , Sakurai Katsunobu , Kimura Kenjiro , Nagahara Hisashi , Amano Ryosuke , Noda Eiji , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Yamada Nobuya , Maeda Kiyoshi , Ohira Masaichi , Ishikawa Tetsuro , Hirakawa Kosei
Published: August 2012

Introduction: Cancer Stem Cells (CSCs) are thought to possess tumor initiation and self-renewal and are associated with tumor progression. The niche cells of microenvironment, such as fibroblast might play an important role for the progression of cancer cells. The aim of this study is to examine the effect of cancer-associated fibroblasts on the stemness of CSCs. Material and Methods: A gastric cancer cell line, OCUM-12, and cancer-associated gastric fibroblast, CaF-37, were used. SP cells, known as CSCs rich population, were isolated from OCUM-12 cells by flowcytometry using Hoechest33342, and were named as OCUM-12/SP. The percentage of SP cells was evaluated by flowcytometry, after it was cultured with condition medium from CaF-37 for three days. SP fraction was evaluated by flowcytometry, in the presence or absence of TGF-β receptor inhibitor, FGF receptor inhibitor, and c-Met Receptor inhibitor. In vivo, tumorigenicity of OCUM-12/SP cells were evaluated by subcutaneous inoculation in the presence or abcence of CaF-37. Results: The inoculation of 1.5x105, 5x104, and 1.5x104 OCUM-12/SP cells with 5x105 CaF-37 fibroblasts resulted in tumor formation in all of mice, respectively. However, the inoculation of 1.5x105, 5x104, and 1.5x104 OCUM-12/SP cells alone results in poor tumor formation at 3(60%) of 5 mice, 0(0%) of 5 mice and 0(0%) of 5 mice, respectively. The percentage of SP fraction of OCUM-12/SP was significantly increased in the presence of condition medium from CaF-37. The increase of SP fraction of OCUM-12/SP cells by condition medium from CaF-37 was inhibited by TGF-β receptor inhibitor, but not FGF receptor inhibitor and c-Met inhibitor. Conclusion: TGF-β from the niche, fibroblasts, might sustain the stemness of CSCs and might be associated with the progression of Cancer Cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3337. doi:1538-7445.AM2012-3337