bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 40: Mutation of EPCAM gene is less frequent in Korean and EPCAM immunohistochemistry can identify Lynch syndrome in patients who do not meet Bethesda criteria.
Authors: Kang So Young , Kang Shin Woo , Do In-Gu , Chang Dong Kyung , Kim Kyoung M. 
Published: August 2014

Abstract
Lynch syndrome is an inherited tumor predisposition syndrome caused by germline mutations of DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Recently, germline deletions affecting the epithelial cell adhesion molecule (EPCAM) gene located upstream of MSH2 were identified as a novel mutational mechanism causing Lynch syndrome. However, most studies were conducted in western populations, where the incidence of CRC is high. To identify the incidence of germline deletions of EPCAM gene in Korea where the incidence of CRC is relatively low and socioeconomic condition is different, we conducted a comprehensive study in 4,993 patients diagnosed and treated with CRCs at a single institute between 2006 and 2011. In all tumor samples, microsatellite instability (MSI) test and immunohistochemistry (IHC) for MMR proteins were performed. In cases with loss of MLH1 protein, methylation of MLH1 by MethyLight was performed and cases with hypermethylation of MLH1 gene were excluded. Germline mutations of MLH1, MSH2 and MSH6 were performed in patients who fulfilled at least one of the revised Bethesda criteria. In 97 patients with loss of MSH2 protein, EPCAM IHC and multiplex ligation-dependent probe amplification for germline deletions of the EPCAM and MSH2 gene were performed. Loss of expression of MMR proteins and/or MSI-high was observed in 337 (6.7%) patients, 112 (2.2%) patients met revised Bethesda criteria, and 54 (1.1%) patients harbored germline mutations of MMR genes. Out of 97 MSH2-negative CRCs, 5 (5.2%) showed concomitant loss of EPCAM expression and EPCAM exon 9 deletionmutations. Out of 5 cases with EPCAM mutation and protein loss, four patients showed familial histories of CRCs. However, one patient showed no family history. In this patient, although multiple liver metastases were the first manifestation, he lived 6 more years after diagnosis. In this large single study cohort, we found that 5.2% of MSH2-negative CRCs were caused by EPCAM deletion mutations, which is lower than previously reported incidences in western populations. Moreover, we could find one candidate patient with de novo mutation of EPCAM gene, which has not been reported yet. Our results strongly support that in routine screening of patients with CRC for Lynch syndrome, a simple and sensitive EPCAM IHC should be included even in cases do not meet Bethesda criteria.
Citation Format: So Young Kang, Shin Woo Kang, In-Gu Do, Dong Kyung Chang, Kyoung M. Kim. Mutation of EPCAM gene is less frequent in Korean and EPCAM immunohistochemistry can identify Lynch syndrome in patients who do not meet Bethesda criteria. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 40. doi:10.1158/1538-7445.AM2013-40
Abstract 400: Coordinated loss of CD9 and IGSF8 expression on the prostate cancer cell surface contributes to metastasis and hormone responsiveness.
Authors: Li Na , Fazli Ladan , Li Estelle , Buttyan Ralph 
Published: August 2014

Abstract
The tetraspanin web is a complex multi-molecular cell structure that tethers cell surface signalling proteins (i.e. integrins) to their intermediate intracellular signalling partners (i.e. small GTPases) and anchors actin filaments. Loss of certain components of the web (CD9, CD82 or CD316) are associated with increased invasive and metastatic behaviors of prostate cancer (PCa) cells and here we demonstrate that two of these tetraspanin web components, CD9 and CD316, also play a role in regulating androgen signaling in PCa cells. Additionally, we utilized human prostate cancer tissue microarrays (TMAs) containing 261 prostate/PCa specimens of differing stages, grades and states of progression (including 60 castration resistant tumors [CRPCs]) to study the relationship between CD9 and CD316 expressions and progression to CRPC. Using androgen-dependent LNCaP cells as a model, we found that androgen deprivation (AD) suppressed expression of CD9 protein and mRNA without affecting CD316 expression. FACS analysis showed that the presence of CD9 on the cell surface was coordinately reduced by AD as was cell surface CD316 which was relocalized to the cytoplasm. This effect was reversed by addition of R1881. Knockdown of CD9 or CD316 in LNCaP cells using siRNA reduced expression of androgen receptor (AR) mRNA but increased expression of PSA, an AR target gene. CD9 or CD316 knockdown also increased LNCaP growth in fetal bovine serum (FBS) containing medium but not in charcoal-stripped FBS (CS-FBS) whereas dual-knockdown further increased growth in FBS as well as in CS-FBS. TMAs immunostained for CD9 or CD316 were assessed for correlation to clinicopathological parameters. For untreated, primary tumors, CD9 and CD316 expression were inversely correlated with Gleason scores (R2=0.9612). CD9 expression was diminished during progression to metastatic (p&lt;0.0038, compared to non-metastatic) and further in CRPC (p&lt;0.040, compared to metastatic non-treated) disease. Conversely, CD316 expression was increased in primary (non-metastatic) as well as in metastatic untreated disease but then reduced (p&lt;0.046) during progression to metastatic CRPC. We propose that androgen deprivation (first line therapy for advanced PCa) may potentially trigger loss of both CD9 and IGSF8 expression on the cell surface that contributes to metastatic behaviors as well as to responsiveness to androgen ablation therapies. This work is supported by the Cancer Research Society (Canada).
Citation Format: Na Li, Ladan Fazli, Estelle Li, Ralph Buttyan. Coordinated loss of CD9 and IGSF8 expression on the prostate cancer cell surface contributes to metastasis and hormone responsiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 400. doi:10.1158/1538-7445.AM2013-400
Abstract 4004: Interaction between bone marrow-derived mesenchymal stem cells and tumor cells induces metallothionein gene expression in human colon cancer.
Authors: Shinagawa Kei , Kitadai Yasuhiko , Yuge Ryo , Onoyama Mieko , Ohnishi Mayu , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: August 2014

Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) are reported to contribute to the formation of tumor stroma. We reported recently that in an orthotopic nude mouse model of human colon cancer, MSCs migrated to tumor stroma, where they differentiated into carcinoma-associated fibroblast (CAF)-like cells and promoted tumor growth and metastasis. Furthermore, the migratory and invasive abilities of KM12SM colon cancer cells were shown by Transwell invasion assay to be enhanced by indirect co-culture with MSCs. However, the molecular mechanisms of this phenomenon have not been elucidated. We performed microarray analysis of gene expression in KM12SM cells and found that expression of metallothionein (MT) mRNA increased markedly by indirect co-culture of KM12SM cells with MSCs. Additionally, in an orthotopic nude mouse model of colon cancer, MT mRNA expression levels were shown to be higher in the tumors produced by KM12SM cells mixed with MSCs than in the tumors produced by KM12SM cells alone. MTs comprise a family of low-molecular-weight, cysteine-rich intracellular proteins that are associated with protection against DNA damage, oxidative stress, and apoptosis. The potential role of MTs in carcinogenesis remains unknown. We examined MT expression in surgical specimens of human colon cancer and colon adenoma by immunohistochemistry. A total of 101 tumors were analyzed. MT immunoreactivity was detected in tumor cells and in atypical stromal cells. Atypical stromal cells with strong MT expression were found in invasive cancers, at the invasive edge, but not in mucosal cancers or adenomas. Levels of MT expression in tumor cells correlated inversely with disease stage. These findings suggest that the interaction between MSCs recruited into tumor stroma and the tumor cells of invasive colon cancers induces and depends on MT expression. Further studies are needed to clarify the specific effects of MTs on tumor cells and stromal cells.
Citation Format: Kei Shinagawa, Yasuhiko Kitadai, Ryo Yuge, Mieko Onoyama, Mayu Ohnishi, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Interaction between bone marrow-derived mesenchymal stem cells and tumor cells induces metallothionein gene expression in human colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4004. doi:10.1158/1538-7445.AM2013-4004
Abstract 4013: S100A4 promotes cell migration and growth through focal adhesion kinase and Src mediated dual signaling pathways in pancreatic cancer cells.
Authors: Cai Guoqiang , Kerr Elizabeth H. , Hu Meng , Yang Youfeng , Buchsbaum Donald J. , Grizzle William E. , Ding Qiang 
Published: August 2014

Abstract
BACKGROUD: Pancreatic cancer is one of the deadliest types of cancer. Activation and expression of focal adhesion kinase (FAK) and Src kinase is abnormally upregulated in pancreatic cancers. The results of clinical trials targeting either Src or FAK by inhibitors are largely unknown. S100A4 is a calcium-binding protein and aberrant S100A4 expression is an independent biomarker for poor outcomes of pancreatic cancer; however, the involved mechanism is unclear.
METHODS: The effects of inhibitors on FAK and Src activation, and on cell migration and growth, were examined in MiaPaca2 and S2VP10 cell lines. To determine whether FAK and Src depend on each other or independently regulate pancreatic cancer cell phenotypes, the effects of FAK or Src mutant expression were determined. The role of S100A4 on FAK and Src activation was evaluated through loss/gain approaches. The association of S100A4 expression with FAK and Src activation was determined by immunostaining on human pancreatic cancer tissue sections.
RESULTS: FAK and Src kinase inhibitors blocked activation in a dose dependent manner in both MiaPaca2 and S2VP10 cells. However, it required more inhibitor to inhibit either FAK or Src in S2VP10 cells. Blocking FAK (or Src) does not completely inhibit Src (or FAK) activation. This is confirmed by the finding that FAK mutant expression completely inhibited FAK activation, but not Src activation. Similarly, Src mutant expression did not inhibit FAK activation. Downregulation of S100A4 expression significantly decreased FAK and Src activation. Importantly, increased S100A4 expression is associated with increased FAK and Src activation in pancreatic cancer.
CONCLUSIONS: These data support that the Src-FAK axis forms a dual signaling pathway, and each of them contributes independently to the aggressive pancreatic cancer cell phenotype. Also, these data support that S100A4 promotes the Src-FAK dual signaling pathway which possibly leads to a feed-forward loop facilitating pancreatic tumor progression.
Citation Format: Guoqiang Cai, Elizabeth H. Kerr, Meng Hu, Youfeng Yang, Donald J. Buchsbaum, William E. Grizzle, Qiang Ding. S100A4 promotes cell migration and growth through focal adhesion kinase and Src mediated dual signaling pathways in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4013. doi:10.1158/1538-7445.AM2013-4013
Abstract 4089: Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases.
Authors: Linn Douglas , Yang Xi , Xie Yingqiu , Alfano Alan , Deshmukh Dhanraj , Wang Xin , Shimelis Hermela , Chen Hegang , Li Wei , Xu Kexin , Chen Mingyuan , Qiu Yun 
Published: August 2014

Abstract
Androgen receptor (AR) plays a pivotal role in prostate cancer. Regulation of AR transcriptional activity by post-translational modifications, such as phosphorylation by multiple kinases, is well documented. Here, we report that two PIM-1 kinase isoforms which are upregulated during prostate cancer progression, namely PIM-1S and PIM-1L, modulate AR stability and transcriptional activity through differentially phosphorylating AR at Serine 213 (S213) and Threonine 850 (T850). Although both kinases are capable of interacting with and phosphorylating AR at S213, only PIM-1L could phosphorylate T850. We also showed that PIM-1S induced S213 phosphorylation destabilizes AR by recruiting the ubiquitin E3 ligase Mdm2 and promotes AR degradation in a cell cycle dependent manner, while PIM-1L-induced T850 phosphorylation stabilizes AR by recruiting the ubiquitin E3 ligase RNF6 and promotes AR-mediated transcription under low-androgen conditions. Furthermore, both PIM-1 isoforms could promote prostate cancer cell growth under low-androgen conditions. Our data suggest that these kinases regulate AR stability and transcriptional activity through recruitment of different functional partners in a phosphorylation-dependent manner. As AR turnover has been previously shown to be critical for cell cycle progression in prostate cancer cells, PIM-1 kinase isoforms may promote prostate cancer cell growth, at least in part, through modulating AR activity via distinct mechanisms.
Citation Format: Douglas Linn, Xi Yang, Yingqiu Xie, Alan Alfano, Dhanraj Deshmukh, Xin Wang, Hermela Shimelis, Hegang Chen, Wei Li, Kexin Xu, Mingyuan Chen, Yun Qiu. Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2013-4089
Abstract 409: In vitro and in vivo characterization of protein biomarkers of metastasis in melanoma.
Authors: Lie Wen-Rong , Becker-Hapak Michelle , Chan Megan , Graham James , Mistry Jehangir , Linette Gerald , Carreno Beatriz 
Published: August 2014

Abstract
Metastasis is a major cause of death in cancer patients. We report here the use of a multiplex proteomic analysis approach to in vitro and in vivo identify biomarkers involved in melanoma invasion/metastasis. An in vitro quantitative profile of the secretome (&gt;200 proteins) was done on non-metastatic melanoma cell lines (A375, LH, M14, DM.6, Lox, and WUmel19) and their metastatic RhoC-expressing counterparts (A375-RhoC, LH-RhoC, M14-RhoC, DM.6-RhoC, Lox-RhoC, and WUmel19-RhoC). A heat map cluster analysis was performed to characterize protein expression levels on metastatic vs. the non-metastatic melanoma cells and identify secreted markers with significantly altered expression that may be involved in tumor invasion, angiogenesis, and metastasis. An in vivo characterization, using an animal model of human melanoma pulmonary metastasis, has identified differential expression of tissue and circulating protein biomarkers in tumor and sera, respectively. Moreover, use of species-specific assays has allowed us to dissect the contribution of stroma (mouse) and tumor (human). Increased expression of a panel of markers, including IL-8, PLGF, FGF-2, follistatin, MMP-1, MMP-9, TIMP-1, TIMP-2, GDF15, NSE, OPN, and MIF was detected in vivo in both tumor and sera, indicating their roles in inducing angiogenesis, tumor invasion and metastasis. Cell signaling pathway multiplex analyses revealed the activation of PI3K/mTOR pathway in the tumor. Elevated levels of phosphorylated targets of PI3K/mTOR pathway, p70S6K (pT412), GSK3α (pS21), GSK3β (pS9), RPS6 (pS235/236), TSC2 (pS939) and mTOR (pS2448) were detected in the pulmonary tumor metastasis. Hence this human melanoma pulmonary metastasis model may prove to be a useful animal model for studying the actions of PI3K/mTOR inhibitors in melanoma metastasis. Altogether, these in vitro and in vivo studies using multiplex proteomic analysis may assist in the discovery of biomarkers and therapeutic targets for human melanoma interventions.
Citation Format: Wen-Rong Lie, Michelle Becker-Hapak, Megan Chan, James Graham, Jehangir Mistry, Gerald Linette, Beatriz Carreno. In vitro and in vivo characterization of protein biomarkers of metastasis in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 409. doi:10.1158/1538-7445.AM2013-409
Abstract 4318: Development of a novel SurrobodyTM that simultaneously activates both death receptors DR4 and DR5 and induces cancer cell death with high potency.
Authors: Milutinovic Snezana , Zhou Sihong , Wimer Carina , Diaz Paul W. , Kashyap Arun K. , Bhatt Ramesh R. , Reed John C. 
Published: August 2014

Abstract
Death receptors of the Tumor Necrosis Factor (TNF) family are found on surface of most cancer cells and their activation typically kills cancer cells through the stimulation of the extrinsic apoptotic pathway. The endogenous ligand for death receptors-4 and -5 (DR4 and DR5) is tumor necrosis factor-related apoptosis-inducing ligand, TRAIL (Apo2L). TRAIL is expressed by many cell types, including Natural Killer (NK) cells that are involved in the immune surveillance and elimination of cells in vivo. Given that most normal untransformed cells are not susceptible to TRAIL-induced apoptosis, activators of death receptors have emerged as promising cancer therapeutic agents.
One strategy to stimulate death receptors in cancer patients has been to use soluble human recombinant TRAIL protein, but this agent has limitations of a short half-life and decoy receptor sequestration. An alternative strategy to evade decoy receptor sequestration and to have improved pharmacokinetic properties is to generate DR4 or DR5 agonist antibodies. To this end, several agonistic monoclonal antibodies have been reported that overcome the limitations of short half-life, but exhibited the limitation of activating only one of the two death receptors. The SurrobodyTM binding protein is a novel therapeutic protein structure based upon the pre-B cell antigen receptor common chain that is capable of being engineered to bind a diversity of targets with high affinity and specificity. We exploited a previously discovered SurrobodyTM that potently activates both DR4 and DR5 in vitro and in vivo. Here we show experimental results for a dual agonist SurrobodyTM that offers a powerful and likely more reliable strategy for cancer therapeutics based on simultaneous stimulation of both TRAIL receptors, DR4 and DR5.
Citation Format: Snezana Milutinovic, Sihong Zhou, Carina Wimer, Paul W. Diaz, Arun K. Kashyap, Ramesh R. Bhatt, John C. Reed. Development of a novel SurrobodyTM that simultaneously activates both death receptors DR4 and DR5 and induces cancer cell death with high potency. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4318. doi:10.1158/1538-7445.AM2013-4318
Abstract 4343: Therapeutic efficacy of different double arms polyethyleneglycol-modified liposome containing doxorubicin on pulmonary metastasis.
Authors: Sugiyama Ikumi , Sadzuka Yasuyuki 
Published: August 2014

Abstract
[Purpose] Metastasis is responsible for most mortality in cancer therapy. Important things of metastatic treatment are not only prevention but also therapy of metastatic tumor. It was indicated that usability of liposomal doxorubicin (DOX) as drug delivery system formulation which were modified with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine dipolyethyleneglycol(different double arms PEG; DDA-PEG) (DDA-LDOX). DDA-PEG had two different PEG lengths, 2000 and 500, in one molecule. In this study, the effect of DDA-LDOX was examined on pulmonary metastasis compared with 1-monomethoxy-PEG(2000)-2,3-distearoylglycerol (PEG2000-DSG) modified liposomal DOX (2000-LDOX).[Methods] The liposomal DOX was prepared by L-α-distearoylphosphatidylcholine, cholesterol, L-α-distearoylphosphatidyl-DL-glycerol and DOX (100:100:60:18 μmol). Liposomal DOX was added 7.5 μmol DDA-PEG or 15 μmol PEG2000-DSG. In anti-metastasis experiment, BDF1 mice were transplanted B16F10 melanoma cells by intravenous inoculation and each liposome (2.5 mg/kg, DOX) was injected at 20, 23 and 26 day after tumor transplantation. After 48 hr from last administration, the mice were dissected and score of pulmonary metastasis was recorded (0∼10, 0: normal). Removed tissues were determined DOX concentration by fluorescence method. In vitro, it was examined DOX uptake into B16F10 melanoma cells from each liposome. [Results and Discussion] Pulmonary metastasis scores of control and 2000-LDOX were 6.5 and 2.6, respectively. In contrast, that of DDA-LDOX was 1.0. Relative pulmonary weight (%) was correlation with metastatic score (R2=0.954) and supported pulmonary metastasis score. DOX concentration of DDA-LDOX was twice higher than that of 2000-LDOX in the lung, namely, it was proved that DDA-LDOX was easy to accumulate in the lung. Especially, it was suggested that DDA-LDOX accumulated into pulmonary metastatic site because DOX concentrations of heart, spleen and kidney were equal level in other group. In the examination of DOX uptake into tumor cells, DOX level in DDA-LDOX group was significantly higher than that in 2000-LDOX group. The data had supported high accumulation into pulmonary metastasis in vivo. In conclusion, it was suggested that DDA-LDOX was useful drug carrier for suppressed pulmonary metastasis since it could have target ability to pulmonary metastasis.
Citation Format: Ikumi Sugiyama, Yasuyuki Sadzuka. Therapeutic efficacy of different double arms polyethyleneglycol-modified liposome containing doxorubicin on pulmonary metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4343. doi:10.1158/1538-7445.AM2013-4343