bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3839: The role of RhoA in human normal mammary epithelial cell immortalization, stem/progenitor cell self-renew, and differentiation
Authors: Zhao Xiangshan , Band Hamid , Band Vimla 
Published: February 2011

Abstract
One of the earliest steps in oncogenic transformation of hMECs involves loss of senescence and continuous proliferation, a process referred to as immortalization. Delineation of biochemical pathways that mediate hMEC immortalization is therefore likely to provide answers to key questions about early breast cancer. RhoA GTPases are central players in many aspects of basic cell biology, There is little knowledge about the role of Rho in early breast cancer. Our recent findings have revealed the potential role of RhoA GTPase in early oncogenic transformation in breast cancer. We demonstrated that overexpression of constitutively-active RhoA, a Rho effector domain mutant, and the wild-type RhoA(WTRhoA), but not a dominant-negative Rho mutant, induces the immortalization of normal hMECs. This is highly significant as in breast and other cancers WTRhoA overexpression is seen but not mutation. Furthermore, we observed immortalization with a RhoA mutant T37A, that fails to interact with well known Rho effectors, Rho kinase, mDia1 and PKN, thus pointing towards a novel pathway that does not involve actin cytoskeleton organization, which may be a late event. In order to identify the molecular mechanism of RhoA-induced immortalization, we performed microarray expression profiling of RhoA-immortalized vs. parental cells and found alterations in expression of several genes (ELF3, ZNF217, S100P were overexpressed; DAB2, CLCA2, TFPI2, ALOX15B were downregulated) previously implicated in immortalization of mammary epithelial cells, and breast cancer progression. Our western blot and RT-PCR results showed that similar to immortal cells, the expression of these genes were altered in breast cancer cell lines. these results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked to cellular transformation and breast cancer.
There is increasing evidence that breast cancer originates in and is maintained by cancer stem cell (CSC) Which has stem cell properties, including self-renewal, tumorigenicity and multi-lineage differentiation capacity. A major hurdle in addressing how normal stem cell become CSC is the lack of in vitro human stem/progenitor cells that are immortal and can be deliberately manipulated to ask questions related to origins of CSC.
Our current work showed that RhoA immortal cells express luminal, myoepithelial, basal, and stem cell markers (K8/18, E-cadherin, ESA, K5, K6, K14, p63, CD29, CD49f). Indicate that these cells may have stem/progenitor cell properties. It is important to further examine the role of RhoA in normal and cancer mammary stem/progenitor cell self-renewal and differentiation.
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 3839.
Abstract 384: Effects of endostar on cell functions and biological characteristics in tumor-derived endothelial cells
Authors: He Yong , Jiang Li 
Published: February 2011

Abstract
Tumor microvessels are essential to tumor formation, growth, and metastasis. Interventions targeting the microvessels would lead to avascular necrosis of tumor cells. Therefore, specifically targeting endothelial cells in tumor vasculature had become one of the most important strategies for cancer therapy. Endostar, a novel recombinant human endostatin with an additional nine-amino acid sequence, is a novel anti-angiogenesis drug. This present study is to determine how endostar affects the behavior of endothelial cells and tumor-derived endothelial cells both in vitro and in vivo. Human umbilical vein endothelial cells (HUVEC) were cultured and differentiated to tumor-derived endothelial cells (Td-ECs) after co-culturing with conditioned medium from A549 cells, a lung cancer cell line. The anti-angiogenesis effects of endostar on Td-ECs were examined by MTT assay, cell migration assay, flow cytometry, and TUNEL assay. Endostar exhibited a significant inhibitory effect both time and dose dependently in Td-EC cells. In addition, Endostar significantly inhibited cell migration and induced G0/G1 and S phase cell cycle arrest and apoptosis. However, under the same concentrations, Endostar has little impact on HUVEC. To study the in vivo effects, a xenograft model in nude mice was established. Endostar was injected intratumorally as localized administration, and tumor growth was closely monitored during the following days. As a result, endostar showed significant anti-angiogenesis effect and tumor growth inhibition. The concentration of Ca2+ in the treatment groups measured by fluorescence spectrometry was elevated significantly compared to that in the control group. This study revealed a novel activity of endostar in inhibiting angiogenesis, more potently in tumor-derived endothelial cells than in normal endothelial cells. This finding suggests the potential use of endostar as cancer therapeutic to be tested in clinical trials.
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 384.
Abstract 3846: Pleiotrophin in the tumor microenvironment induces expression of VEGFR2 on macrophages and promotes an anti-inflammatory phenotype
Authors: Lynn Kristi D. , Roland Christina L. , Dineen Sean P. , Sullivan Laura A. , Brekken Rolf A. 
Published: February 2011

Abstract
Macrophages are an abundant immune cell in the tumor microenvironment that contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor-A (VEGF). We are interested in investigating the effects of VEGF inhibition on macrophages and other stromal cells within the tumor. We demonstrated recently that macrophages (systemic and tumor associated) in tumor-bearing animals express VEGFR2 in contrast to macrophages from non tumor-bearing animals. Furthermore, we found that selective inhibition of VEGFR2 inhibits macrophage infiltration into tumors in vivo. These results demonstrate that when VEGFR2 is expressed on macrophages it is the dominant receptor driving VEGF-induced migration in vitro and in vivo. Additionally, we found that the cytokine pleiotrophin (PTN) is sufficient to induce VEGFR2 expression on macrophages. PTN is expressed by many human breast cancer cells (e.g., MDA-MB-231) and the majority of human primary breast tumors. However, the connection between PTN and macrophage phenotype is still unexplored. Macrophages can be divided into two functional sub-types: M1 or classically activated macrophages and M2 or alternatively activated macrophages. M1 macrophages are powerful effector cells that produce pro-inflammatory cytokines and are capable of destroying tumor cells. In contrast, M2 macrophages inhibit the inflammatory response and promote tumor growth and angiogenesis. We employed the MMTV-PyMT transgenic, spontaneous breast cancer model to characterize PTN expression, immune cell infiltration, and immune cell function during the course of tumor progression. We found that PTN levels correlate with VEGFR2+ macrophage and M2 macrophage levels, which all peak during the transition from hyperplasia to early malignancy. Whereas, MDSC and Treg levels as well as levels of the anti-inflammatory cytokines IL-10 and IL-1β peak during the early carcinoma stage. We identified that PTN not only induces VEGFR2 expression by macrophages but also promotes an M2 phenotype in vitro. In addition, we have evidence that VEGF can modulate the level of PTN expression through VEGFR1. These results suggest a mechanism through which anti-VEGF therapy modulates PTN and M2 macrophage levels in vivo. Based on these observations, we hypothesize that PTN is a critical cytokine involved in breast tumor progression through promotion of a VEGFR2+, M2 macrophage phenotype in the tumor microenvironment.
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 3846.
Abstract 3849: Mast cell inhibition by Btk inhibitor PCI-32765 as a potential cancer therapy
Authors: Soucek Laura , Honigberg Lee , Kortlever Roderik , Buggy Joseph , Swigart Lamorna , Evan Gerard I. 
Published: February 2011

Abstract
An association between inflammation and cancer has long been recognized but the cause and effect relationship linking the two remains unclear. Myc is a pleiotropic transcription factor that is over-expressed in many human cancers and instructs multiple extracellular aspects of the tumor tissue phenotype, including remodeling of tumor stroma and angiogenesis. We have shown in a
β cell tumor model that Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site, a recruitment that is absolutely required for macroscopic tumor expansion. Indeed, such tumors did not grow in mast cell deficient mice. Furthermore, treatment of established β cell tumors with cromolyn, a stabilizer that prevents mast cell degranulation, rapidly triggered hypoxia and cell death of tumor and endothelial cells. Inhibitors of mast cell function may therefore prove therapeutically useful in restraining expansion and survival of pancreatic cancer. However, such compounds have not yet been developed for systemic administration and applications in cancer therapy. In fact, there are no clinically effective mast-cell blockers. Therefore, we tested PCI-32765 (Pharmacyclics, Inc.), a Bruton's tyrosine kinase (BTK) inhibitor in clinical trials for B cell non-Hodgkin's lymphoma, for its ability to inhibit mast cell function and tumorigenesis in our mouse model of β cell neoplasia. Here we show that long term treatment with PCI-32765 prevents mast cell degranulation and causes tumor regression and vasculature collapse. Surprisingly, the compound also displays an unexpected anti-proliferative effect on tumor cells - but not surrounding normal tissue - which is still under investigation. Our results once more support the idea that mast cell inhibition could be beneficial in the treatment of insulinomas and possibly other pancreatic cancers and suggests that PCI-32765 could open the way to clinical studies assessing this potential.
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 3849.
Abstract 3858: Synergistic antitumor effects of combination therapy with S-1 and HER2 targeting agents in gastric cancer with HER2 amplification
Authors: Tanizaki Junko , Okamoto Isamu , Takezawa Ken , Tsukioka Sayaka , Uchida Junji , Kiniwa Mamoru , Fukuoka Masahiro , Nakagawa Kazuhiko 
Published: February 2011

Abstract
HER2 amplification is observed in 20-30% of gastric cancer and it has been correlated to poor outcomes and more aggressive disease. Combination therapies with HER2 targeting agents and cytotoxic agents are considered a therapeutic option for patients with HER2 amplified gastric cancer. We now investigated the effects of the combination treatment with S-1(or 5-fluorouracil (5FU)) and either lapatinib or trastuzumab on the growth of gastric cancer cells with or without HER2 amplification in vitro and in vivo. The combination of 5FU and either lapatinib or trastuzumab showed a synergistic antiproliferative effect in HER2 amplified gastric cancer cells. Combined treatment with 5FU and lapatinib or trastuzumab induced synergistic increases in the number of apoptotic cells and in the activity of caspase-3 in HER2 amplified cells, wheareas, such synergistic antiproliferative effect nor the enhancement of apoptosis was observed in cells without HER2 amplification. Thymidylate synthase (TS) is an important target enzyme for 5FU, with a reduced level of TS expression having been associated with a higher rate of response to 5FU-based chemotherapy. To elucidate the molecular mechanism of the synergistic effect by the combination of 5FU and lapatinib or trastuzumab, we examined the effects of lapatinib or trastuzumab on the expression and activity of TS in gastric cancer cells. Both lapatinib and trastuzumab induced down-regulation of TS expression and inhibition of TS activity in HER2 amplified cells, whereas neither lapatinib nor trastuzumab has such effects on TS expression and activity in cells without HER2 amplification. Similar to the effects of lapatinib or trastuzumab, TS depletion by siRNA resulted in the enhancement of 5FU-induced apoptosis, suggesting that TS down-regulation attributes, at least in part, to the synergistic proapoptotic interaction with 5FU. Furthermore, the combination of oral fluoropyrimidine S-1 and lapatinib or trastuzumab synergistically inhibited the growth of gastric cancer cell xenografts with HER2 amplification. Our results thus suggest that the combination of S-1 and lapatinib or trastuzumab has synergistic antitumor effects in HER2 amplified gastric cancer cells and that effect is likely attributable to the down-regulation of TS expression and inhibition of TS activity by lapatinib or trastuzumab. In conclusion, these observations provide a basis for clinical evaluation of combination chemotherapy with S-1 and HER2 targeting agents, lapatinib or trastuzumab, in gastric cancer patients with HER2 amplification.
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 3858.
Abstract 3861: A genome-wide association study of upper aerodigestive tract cancers identifies 4q21, 4q23, and 12q24 as susceptibility loci
Authors: McKay James D. , Truong Therese , Lathrop Mark , Brennan Paul ,   on behalf of the INHANCE consortium.
Published: February 2011

Abstract
To identify risk variants for upper aero-digestive tract (UADT) cancers, we performed a genome-wide association study of 2,091 UADT cancer cases and 8,334 controls followed by replication of 20 variants in an additional 6,545 UADT cancer cases and 7,892 controls. Five common variants presented evidence for significant association in the replication series (one sided p ≤ 0.005 - preplication) and combined analysis (p ≤ 5×10−7 - pcombined). Three variants were in the alcohol dehydrogenase (ADH) gene cluster on 4q23 (rs1573496-ADH7, preplication=7×10−10 /pcombined=5×10−17 rs1229984-ADH1B, preplication=3×10−10 pcombined=5×10−21 and rs698-ADH1C, preplication=0.003 pcombined=3×10−7). The fourth variant (rs4767364, preplication=4×10−4/pcombined=7×10−8) was located in an extended linkage disequilibrium region at 12q24 that contains the aldehyde dehydrogenase 2 (ALDH2) gene and appears to have effects similar, albeit more modest, to that observed with heterozygote ALDH2 null allele (rs671) common in Asian populations. The fifth variant (rs1494961, preplication=9×10−6 pcombined=2×10−8) was located near DNA repair related genes HEL308 and FAM175A (or Abraxas) at 4q21. This 4q21 variant was also associated with lung cancer risk in a series of 5,652 lung cancer cases and 9,338 controls (rs1494961, p=3×10−4). These results further highlight the importance of the genes involved in the metabolism of alcohol in UADT cancer susceptibility, and also implicate 4q21 in susceptibility to both UADT and lung cancers.
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 3861.
Abstract 3862: Identification of a novel genetic variant in the KLK3 gene which predisposes to prostate cancer
Authors: Kote-Jarai Zsofia , Al Olama Ali Amin , Leongamornlert Daniel , Tymrakiewicz Malgorzata , Saunders Ed , Guy Michelle , Mahmud Nadiya , Giles Graham , Severi Gianluca , Hopper John , Hamdy Freddy , Neal David , Donovan Jenny , Muir Kenneth , Morrison Jonathan ,   The UK Genetic Prostate Cancer Study Collaborators/BAUS Section of Oncology, Easton Douglas , Eeles Rosalind 
Published: February 2011

Abstract
Prostate cancer (PrCa) is the commonest solid tumour in men in developed countries. To identify common PrCa susceptibilility alleles, we conducted a multistage genome-wide association study (GWAS). In the first stage (stage 1) 541,129 SNPs were genotyped using the Illumina Infinium platform in 1,854 PrCa cases with clinically detected PrCa diagnosed at &lt;60 years or a family history of disease, and 1,894 population screened controls with low (&lt; 0.5ng/ml) prostate specific antigen (PSA) level from the UK. We identified 7 novel PrCa susceptibility loci (P=2.2×10−8 to P=8.1×10−29) one of which contains a strong candidate susceptibility gene KLK3 which codes for PSA. PSA is widely used as a biomarker for PrCa detection and disease monitoring. The tag-SNP in this region, rs2735839, was associated with both PrCa disease (P=1.33×10−20) and with PSA level (P =6× 10−8). To refine the association of PrCa with variants in this region we imputed genotypes for SNPs that were not in our GWAS study, using the Mach program and the HapMap 2 CEU population as a reference panel. Among SNPs in the KLK3 region, the strongest evidence for association with PrCa cancer was observed for rs17632542, (P =5.9×10−26), a SNP not typed in the GWAS. We genotyped this novel SNP in our stage 1 (as above) and an additional stage2 sample set of 3650 PrCa cases and 3940 controls from the UK and Australia, not selected for PSA level, using Taqman assay and ABIPrism 7900HT sequence detection system. rs1763542 showed stronger evidence of association than the original tag-SNP in both stages (stage 2 P=2×10−5, overall P=3.2×10−31). Whereas rs2735839 is intergenic between the KLK3 and KLK2 genes, rs17632542 is a non-synonymous coding SNP in the KLK3 gene causing an Ile to Thr substitution at aa179. We conclude that this SNP more strongly associated with PrCa then other known SNPs in the KLK3 region, and is a strong candidate for a causative variant influencing PrCa risk.
Acknowledgements: This study was funded by Cancer Research UK, The Prostate Cancer Research Foundation, and NIHR support to the Biomedical Research Centre.
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 3862.
Abstract 3868: Long-term inhibition of cells at metaphase with intact mitotic spindles results in unscheduled chromatid separation and catastrophic arrest in mitosis
Authors: Daum John R. , Sivakumar Sushama , Daniel Jeremy J. , McAvoy Jennifer N. , Potapova Tamara A. , Gorbsky Gary J. 
Published: February 2011

Abstract
In the presence of unaligned chromosomes or other spindle abnormalities, the mitotic spindle checkpoint blocks both chromatid separation at anaphase and exit from mitosis. The spindle checkpoint is sustained by signaling from kinetochores that are not properly attached to microtubules of the mitotic spindle. Normally, when chromosomes align at the spindle equator at metaphase, microtubule-kinetochore interactions act to extinguish checkpoint signaling. The cessation of the checkpoint signal activates the Anaphase-Promoting Complex/Cyclosome (APC/C), an E3 ubiquitin ligase. The APC/C ubiquitylates the mitotic effectors, securin and cyclin B, which are then degraded by the proteasome. Securin and cyclin B degradation initiates chromatid separation at anaphase and triggers mitotic exit. We have found that long-term arrest of Hela cells with their chromosomes aligned at the metaphase plate results in chromatid separation without mitotic exit. Recently, we and others have characterized C13orf3/Ska3, a newly discovered component of the Ska (Spindle and kinetochore-associated) protein complex. We found that in mitosis Ska3 protein accumulates at kinetochores reaching maximal levels at metaphase. Upon anaphase onset, kinetochore-associated Ska3 levels decline and are eventually lost at telophase. We demonstrated that cells depleted of Ska3 by RNAi achieve metaphase alignment but fail to silence the spindle checkpoint. During this mitotic arrest with chromosomes aligned at the metaphase plate, kinetochores retain robust microtubule attachments. Kinetochores within these Ska3-depleted cells accumulate abnormally high levels of the mitotic spindle checkpoint protein, Bub1, presumably accounting for the inability to silence the checkpoint. Under extended metaphase arrest, the chromatids of individual chromosomes eventually separate, but cells remain arrested in mitosis. To test if other means of inducing metaphase arrest would also lead to chromatid separation, we treated cells in mitosis with the proteasome inhibitor, MG132. Again, after several hours at metaphase, chromatids separated. We speculate that for cells arrested at metaphase, continual pulling forces of the kinetochores on the mitotic spindle eventually overcomes the cohesin complex that holds chromatids together. This “cohesin slippage” results in abnormal chromatid separation for cells still in mid-mitosis. This response reflects a novel terminal phenotype for cells arrested in mitosis with an intact mitotic spindle. (Supported by the NIGMS and the McCasland Foundation.)
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 3868.