bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1015: Head and neck cancer expression of YAP65: A novel oncogene
Authors: Ge Lin , Ge Lin , Meng Wenxia , Zhou Hongmei , Bhowmick Neil 
Published: February 2011

Abstract
Yes-associated protein (YAP), a transcription coactivator associated with maintaining tissue size, is reported as an oncogene in many types of cancer including ovarian, liver, lung, colon and prostate. However, the role of YAP in head and neck carcinomas is not known. Our objective was to explore the role of YAP in head and neck carcinomas. We found YAP overexpressed in the epithelial and stromal compartments of head and neck carcinomas compared to benign tissues in 140 samples. Interestingly, the squamous cell carcinomas, had elevated YAP expression in the epithelial cytoplasm in 36% of the patients. However, we observed both cytoplasmic and prominently nuclear localization of YAP in the adenocarcinomas. The tumor microenvironment is widely accepted as a promoter of tumor progression, where carcinoma-associated fibroblasts (CAFs) constitute the majority of cells. In the stroma, YAP was found to be expressed in endothelial cells and some heterogenously within the CAF population. As reported for prostate cancer, we found the transforming growth factor-beta (TGF-ß) receptor type II expression to be lost in the head and neck cancer-associated stromal cells. Since YAP has never been reported to be associated with CAFs, we performed in vitro experiment to determine the relationship of YAP and TGF-ß signaling in primary stromal cells associated with benign and head and neck cancer cells. We found TGF-ß1 can promote YAP expression and nuclear localization in normal fibroblasts. The oral human CAFs have differential expression of YAP and α-smooth muscle actin (α-SMA). Although CAFs are commonly characterized by their expression of α-SMA, YAP-expressing CAFs expressed less α-SMA and α-SMA-expressing CAFs expressed less YAP in seven independent CAF lines developed. However, all of these heterougenous head and neck CAF lines had the loss of TGF-ß receptor type II expression and concomitant upregulation of Wnt5a. Interestingly, those CAFs expressing YAP had 2-fold greater Wnt5a expression. In conclusion YAP expression is differentially expressed in adeno- and squamous cell carcinomas of head and neck carcinomas, and is heterogenously expressed in the associated CAF. YAP may regulate Wnt5a as a paracrine factor, reported to promote the progression of oral carcinomas, in a TGF-ß dependent and independent manner.
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 1015.
Abstract 1018: Analyzing αvβ8 integrin functions in mouse and human glioma cells
Authors: Tchaicha Jeremy H. , McCarty Joseph H. 
Published: February 2011

Abstract
In this study we aim to determine the functional roles for αvβ8 integrin in glioblastoma multiforme (GBM)-induced angiogenesis. These studies originate from our analyses of αvβ8 integrin in developmental brain angiogenesis. αv and β8 knockout (KO) mice develop brain-specific vascular phenotypes that resemble vascular pathologies observed in GBM. Thus, we hypothesize that altered αvβ8 integrin expression and/or function in tumor cells leads to vascular pathologies like those in GBM. Indeed, a murine xenograft model of astrocytoma suggested a role for the integrin in glioma-induced angiogenesis. Primary mouse astrocytes were cultured from wild type (WT) and β8 KO neonates to be immortalized (HPV:E6/E7) and transformed (HRas:G12V). WT and β8 KO transformed astrocytes were intracranially injected into athymic mice. WT tumors displayed pathological features of grade III astrocytomas, whereas β8 KO tumors resembled grade IV GBMs. KO tumors contained widespread edema and hemorrhage as well as pathological angiogenesis, as assessed by quantitation of microvascular density. Interestingly, astrocyte transformation resulted in a significant reduction in αvβ8 integrin cell surface expression in WT cells. Additionally, WT mouse transformed astrocytes lost αvβ8 integrin expression after approximately eight passages in vitro. Exogenous expression of β8 integrin in β8 KO transformed astrocytes resolved the pathologies observed in KO tumors giving further credence to the idea that loss of αvβ8 integrin expression correlates with tumorigenic potential of oncogene-transformed astrocytes. To compliment our mouse model, several established human glioma cell lines were characterized for expression of αvβ8 integrin protein. Some of the cell lines displayed diminished expression of αvβ8 integrin, whereas others showed increased levels, as compared to non-malignant human astrocytes. Intracranial implantation of high and low β8 integrin-expressing human glioma cell lines resulted in tumors exhibiting similar phenotypes to those observed in the mouse model; low expressers were marked by vascular pathologies indicative of β8 KO mouse tumors. Upon overexpression of β8 integrin in a low β8 integrin-expressing human glioma cell line, angiogenic pathologies were largely resolved. Collectively, these data suggest an important functional role for αvβ8 interin in glioma angiogenesis.
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 1018.
Abstract 1020: Combined effects of BCL-2 pathway gene variants on the risk of endometrial cancer: results from Shanghai Endometrial Cancer Study
Authors: Dorjgochoo Tsogzolmaa , Long Jirong , Xiang Yong-Bing , Cai Qiuyn , Cai Hui , Cheng Jiarong , Zheng Wei , Shu Xiao-ou 
Published: February 2011

Abstract
The BCL-2 pathway genes may play important roles in regulation of apoptosis. It has been suggested that overexpression of the antiapoptotic Bcl2 gene variants associated with the risk of endometrial cancer. Proapoptotic BAX, BAK, BAD are believed to diffuse in cell carcinogenesis. We hypothesized that single-nucleic polymorphisms (SNPs) in the Bcl-2 pathway genes including Bcl2, BAX, BAD and BAK1 may be associated with endometrial cancer risk. Included in this study were 1,028 endometrial cancer cases and 1,003 controls from the Shanghai Endometrial Cancer Study. A total of 77 tagging SNPs were genotyped for these genes using the Affymetrix MegAllele Targeted Genotyping system. A logistic regression was used to estimate the association between SNPs and the cancer risk. Genetic risk score (GRS) was calculated using a simple count method that included the SNPs that showed significant associations and are not in LD with each other (r2 &lt;0.8). Significant associations with cancer risk were found for SNP rs477895 in the BAD gene and 7 SNPs in the Bcl2 gene, including rs7243091, rs7230177, rs7231901, rs17759659, rs4941195, rs2279115 and rs1944423. Women carrying the minor homozygous and heterozygous genotypes of SNPs including rs7243091, rs17759659, rs4941195, rs2279115 and rs1944423 have an increased risk of endometrial cancer (age adjusted odds ratio [OR] range, 1.2-2.1; P trend &lt;0.05 for all), compared with women carrying the major homozygous genotypes. For SNPs rs7230177 and rs7231901, a decreased risk was observed among individuals carrying minor homozygous genotype and heterozygous compared with the major genotype (P trend &lt;0.01). Haplotype analyses of the Bcl2 gene showed two haplotypes, GTCGCTG and ACAAATG were associated with a significant increase in risk of endometrial cancer (P value &lt;0.05). The risk of endometrial cancer tended to increase with higher GRS (based on 5 SNPs of the Bcl2) (multivariate OR=1.96, 95% CI: 1.44-2.65 for ≥5 vs. ≤1 GRS, P trend &lt;0.01). This increased risk was stronger among postmenopausal or obese (BMI ≥27.5) women than among premenopausal or non-obese women (P trend &lt;0.05 for both). These findings suggest that BCL-2 pathway genes, particularly Bcl2 genetic variations are significantly associated with an increased risk of endometrial cancer among Chinese women. A GRS which combines information from several variants of Bcl2 gene might have a potential to identify the women at a high risk of endometrial 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 1020.
Abstract 1023: Cytoplasmic domain of interferon-gamma receptor beta chain (IFNγR2) has an antiapoptotic activity as a Bax inhibitor
Authors: Gomez Jose , Sun Weiyong , Gama Vivian , Hajkova Dagmar , Yoshida Tomoyuki , Wu Zhengrong , Pink John , Jackson Mark , Miyagi Masaru , Matsuyama Shigemi 
Published: February 2011

Abstract
Bax is a pro-apoptotic protein mediating intrinsic cell death signal. New Bax inhibitor was searched by using yeast-based functional screening, and Interferon Gamma Receptor Beta chain (IFNγR2) was cloned as a Bax suppressor. IFNγR2 is a receptor protein, which is a part of the IFNγ receptor complex with IFNγR1, involved in the Jak/STAT signaling pathway. Upon IFNγ binding a conformational change in the receptor complex occurs, followed by activation of Jak kinases, and STAT1. We found that the C-terminus region of IFNγR2 amino acids 296-337 (IFNγR2296-337) contains the novel Bax inhibiting domain. This portion does not contain the Jak2 binding domain, therefore IFNγR2 anti-apoptotic function is independent of the well characterized JAK/STAT signaling. IFNγR2296-337 rescued human cells from apoptosis induced by overexpression of Bax, but not Bak. Overexpression of IFNγR2 (wild type and IFNγR2296-337) rescued cells from apoptosis induced by Etoposide and Staurosporine that are known to activate Bax-mediated cell death. Interestingly, IFNγR2 inhibited apoptosis induced by the BH3 only protein Bim-EL, suggesting that IFNγR2 inhibits Bax activation by BH3 protein. The binding of Bax and the C-terminus of IFNγR2 was confirmed by co-immunoprecipitation using cell lysate and binding experiments using purified recombinant proteins. Interestingly, recombinant Bcl-2 protein competed with IFNγR2 to bind Bax in cell lysates, suggesting that IFNγR2 and Bcl-2 share a similar mechanism to bind Bax. We found that the C-terminal fragment (cytoplasmic domain) of IFNγR2 is expressed in the cytosol of transformed, and in some human prostate cancer cell lines (PC3, and DAMI cells). Our preliminary study suggests that the cytoplasmic IFNγR2 C-terminal fragment is produced by proteolytic cleavage of IFNγR2 at the plasma membrane. The cytoplasmic IFNγR2 fragment may have a certain role to confer cancer cells resistant to apoptotic stress. The discovery of anti-Bax activity of the cytoplasmic domain of INFγR2 may shed new light on the mechanism of how cell survival is controlled by IFNγ and Bax.
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 1023.
Abstract 1029: BB a novel Bim isoform upregulated in acute lymphoblastic leukemia after glucocorticoid monotherapy confers a novel apoptosis regulation mechanism
Authors: Trockenbacher Alexander , Mansha Muhammad , Ploner Christian , Kofler Reinhard 
Published: February 2011

Abstract
Glucocorticoids (GCs) are fundamental components of most chemotherapies employed against lymphoid malignancies because they cause apoptosis and cell cycle arrest. In this study we investigate the possible role of a novel splice variant of human BCL2L11/Bim, termed BB, for GC-induced apoptosis. First evidence for BB was obtained by Affymetrix-based whole genome comparative expression profiling, where a corresponding probe set was found to be induced in 8 of the 13 ALL children and 1 adult during systemic GC monotherapy (Schmidt et al., 2006). The postulated BB mRNA consists of the 5’ portion of Bim (up to and including the BH3-containing exon 8) and the 3’ portion of Bam, a cDNA originally discovered in a multiple myeloma cDNA library (Claudio et al., 2002). Thus, it encodes a putative protein consisting of the N-terminal region of Bim (including its BH3 domain) and 40 C-terminal amino acids derived from Bam and not present in any known Bim transcript. BB and Bim proteins have similar molecular masses and could not be distinguished by conventional Western technology when probed by α-Bim antibody as most α-Bim antibodies recognize the N-terminal region which is common to both isoforms. RT-PCR data and protein analyses carried out by using α-Bam antibody (that recognizes the Bam specific C-terminal region) on GC-treated CEM-C7H2 cells supported the existence of the postulated BB mRNA and protein. Subcellular localization analysis of BB suggested that BB may be directed to mitochondria, ascribed probably to its BH3-domain interaction with other BCL2 proteins and not by its unique C-terminus which in contrast to the Bim C-terminus doesn't localize to mitochondria. The functional analyses with conditional overexpression in ALL in vitro model revealed that overexpressed BB is a killer protein with potency similar to that of Bim and thus may contribute to the anti-leukemic effects of GCs and perhaps other apoptotic responses.
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 1029.
Abstract 1034: Combination therapy with gossypol reveals synergism against gemcitabine resistance in cancer cells with high Bcl-2 expression
Authors: Wong Foong Ying , Liem Natalia , Wang Lingzhi , Xie Chen , Yong Wei Peng 
Published: February 2011

Abstract
Gemcitabine is an anticancer agent used in breast, non-small cell lung, pancreatic and ovarian cancer. However, many cancers have been showed to be resistant to gemcitabine. Recent studies have demonstrated that gemcitabine resistance can be overcome when combined with gossypol. Gossypol is an inhibitor of Bcl-2 that induces apoptosis in various cancer cell lines. The aim of our study was to determine whether gossypol can overcome gemcitabine resistance via its interaction with the Bcl-2 protein. IC50 of gossypol and gemcitabine, as well as baseline expression of Bcl-2 were determined in 10 cell lines derived from nasopharyngeal (n=4), breast (n=3) and gastric (n=3)cancers. High Bcl-2 baseline expression that was observed in 3/10 cell lines, had higher IC50 to gemcitabine. Upregulation of Bcl-2 levels were also observed after treatment in cell lines that high Bcl-2 baseline expression. These findings suggest an interaction between Bcl-2 protein and gemcitabine resistance. Furthermore, in 7/10 cell lines that were sensitive to gemcitabine, five showed low Bcl-2 expression, suggesting that Bcl-2 levels plays a role in gemcitabine response in cancer. To determine whether gossypol can overcome gemcitabine resistance, combination treatments were carried out either by adding the drugs simultaneously or sequentially to the cell lines. Dual drug treatment was found to be synergistic to cell lines that have both high Bcl-2 level and were resistant to single agent, gemcitabine. Intrestingly cell lines that were sensitive to both drugs, and had high Bcl-2 level were also synergistic when treated with the combined drugs. In contrast, cell lines that were sensitive to both drugs and had low Bcl-2 level were antagonistic to combined drug treatments. The (-) enatiomer of gossypol (AT101) has been reported to be more potent than gossypol in inhibiting cell growth and inducing apoptosis in cancer cells. This suggests that AT101 is a more effective drug than gossypol in overcoming gemcitabine resistance. Cell lines treated with AT101 had lower IC50 compared to those treated with gossypol. Two cell lines (HK1 and AGS) that were intermediate responders to gossypol demonstrated higher sensitivity when treated with AT101, suggesting that AT101 is a more effective drug than gossypol. Futhermore, in vitro durg response studies comparing the 2 drugs in 35 gastric cell lines reveals an overall hypersensitive to AT101 compared to gossypol. Current studies are underway to investigate combination treatment of AT101 with gemcitabine, as well as its interactions with the Bcl-2 family proteins.
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 1034.
Abstract 1036: ARC synergizes with ABT-737 to induce apoptosis in human cancer cells
Authors: Bhat Uppoor , Pandit Bulbul , Gartel Andrei L. 
Published: February 2011

Abstract
Previously, we reported that the nucleoside analog/transcriptional inhibitor ARC was able to induce p53-independent apoptosis in multiple cancer cell lines of different origin. This occurred at least in part by the suppression of Mcl-1 expression, which a short-lived, pro-survival member of the Bcl-2 family. Interestingly, pan-caspase inibitor Z-VAD-FMK protected leukemia cells from ARC-induced mitochondrial damage and apoptosis, and Mcl-1 mRNA and protein from down-regulation by ARC. At the same time treatment of human cancer cells with the pan-Bcl-2 inhibitor ABT-737 alone led to up-regulation of Mcl-1 protein expression. Combination of sub-apoptotic concentrations of ABT-737 and ARC suppressed Mcl-1 expression, induced mitochondrial injury and potent apoptosis in wide variety of human cancer cell lines. In prostate cancer cells co-treatment with ARC and ABT-737 resulted in synergistic induction of cell death with combination index 0.7-0.8. These data suggest that ABT-737/ARC combination that simultaneously targets Bcl-2 and Mcl-1 may be efficient against human 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 1036.
Abstract 1038: Defining the mechanism by which melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24)-induced autophagy switches to apoptosis in prostate cancer cells
Authors: Bhutia Sujit K. , Dash Rupesh , Azab Belal , Das Swadesh , Su Zhao-zhong , Lee Seok-Geun , Grant Steven , Dent Paul , Curiel David T. , Sarkar Devanand , Fisher Paul B. 
Published: February 2011

Abstract
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a unique member of the IL-10 gene family, displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis, and modulation of an anti-tumor immune response. Apoptosis induction by mda-7/IL-24, when delivered by an adenovirus (Ad. mda-7), involves an endoplasmic reticulum (ER) stress response and generation of ceramides. Additionally, Ad. mda-7 promotes autophagy in certain cancer cell types. In the present study, we document that Ad-mda-7-induced ER stress and ceramide generation result in induction of autophagy in prostate cancer cells, without affecting normal human prostate epithelial cells, via the canonical autophagic pathway, involving Beclin-1, atg5 and hVps34. Autophagy is evident until 24 h post Ad. mda-7-infection and then switches to apoptosis at 48 h. Inhibition of autophagy by 3-methyladenosine (3-MA) significantly increases Ad. mda-7-induced apoptosis suggesting that autophagy might first be initiated as a cytoprotective mechanism in prostate cancer cells. Inhibition of apoptosis by overexpression of anti-apoptotic proteins Bcl-2 or Bcl-xL increases autophagy upon Ad. mda-7 infection. During the apoptotic phase, MDA-7/IL-24 protein physically interacts with Beclin-1 and this interaction might inhibit Beclin-1 function culminating in apoptosis. Conversely, Ad. mda-7 infection leads to calpain-mediated cleavage of ATG5 protein that might also facilitate a biochemical switch from autophagy to apoptosis. Our present studies reveal novel aspects of interplay between autophagy and apoptosis that underlie the cytotoxic action of mda-7/IL-24 in prostate cancer cells. These new insights into mda-7/IL-24 action provide interesting leads for developing innovative combinatorial approaches for prostate cancer therapy.
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 1038.
Abstract 104: Breast cancer stem cell extinction models: Implications for HER2 targeted therapy
Authors: Riley Lindsay A. , Zhou Hua , Lange Kenneth , Sinsheimer Janet S. , Sehl Mary E. 
Published: February 2011

Abstract
Treatment with trastuzumab therapy has been shown to dramatically improve survival and reduce recurrence of breast cancer in patients with overexpression of HER-2/neu. A subpopulation of cells in human breast tumors has been identified with characteristics of cancer stem cells. These breast cancer stem cells (BC SCs) have been recently shown to have increased expression of HER-2/neu, suggesting that BC SCs might have a chance of being eradicated with therapy targeting HER-2. We propose a mathematical model to examine the feasibility of eradicating breast cancer stem cells with HER-2 targeted therapy. Using a linear birth-death process model, we can predict the likelihood that BC SCs have become extinct after a year of trastuzumab therapy. We examine the effects of varying degrees of HER-2/neu overexpression and susceptibility of BC SCs to trastuzumab therapy by changing the death rates under targeted therapy (see Table). We also quantify the average time to extinction of BC SCs and the average number of BC SCs remaining after a year of therapy. We conclude that trastuzumab may be effective in eradicating BC SCs in the adjuvant therapy setting, even in patients in whom the bulk of the tumor population does not overexpress HER-2/neu.BC SC population size and extinction likelihood for varying death rates.Death rate (per week)Mean extinction time (SD) (weeks)Probability of extinction in 1 year (52 weeks)0.3433 (4.1)0.9990.3038 (4.6)0.9900.2841 (5.0)0.9720.2644 (5.4)0.9220.2448 (5.9)0.7950.2253 (6.5)0.5250.2059 (7.3)0.1640.2066 (8.2)0.0060.1676 (9.4)&lt;0.0001
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 104.