bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 138: Novel PAK4 allosteric modulators (PAMs) provide potential therapeutic options in human gastric cancer
Authors: Chien Wenwen , Xiao Jinfen , Ding Ling-Wen , Muzakar Muhammad Ikhsan B. , Sun Qiao-Yang , Gery Sigal , Senapedis William , Shacham Sharon , Baloglu Erkan , Koeffler H. Phillip 
Published: August 2015

Abstract
Expression of PAK4 (p21-activated serine/threonine kinase 4) is associated with gastric tumorigenesis. Overexpression of PAK4 is correlated with metastasis of gastric cancer and in part confers cisplatin resistance in gastric cancer patients. We transduced the human gastric cancer cell line AGS with CRISPR/cas9 targeting PAK4, and observed reduced cell proliferation and motility. Novel PAK4 allosteric modulators (PAMs) were evaluated for their potential therapeutic use for gastric cancer. A panel of human gastric cancer cell lines was screened with four PAMs (KPT-7189, -7349, -7657, -8752). MTS assay showed inhibition of cell viability by PAMs in 6 of 10 gastric cancer cell lines (IC50 ranged from 50 to 5000 nM). Cell cycle analysis and annexin V assay indicated a combination of cell growth arrest at G1 phase and cell apoptosis after treatment with PAMs. Furthermore, PAMs diminished expression levels of PAK4, induced apoptosis-related molecule caspase-3, and suppressed PI3K/Akt and MEK/Erk signaling. Wound assay showed inhibition of cell migration and soft agar assay demonstrated suppression of colony formation for gastric cancer cells treated with PAMs. Mouse xenograft models are currently under investigation. Remarkably, PAMs in combination with cisplatin induced cell death in cisplatin-resistant gastric cancer cells in a synergistic manner. This study demonstrates PAMs have anti-tumor activity against gastric cancer cells and suggests their potential use for the treatment of gastric cancer.
Citation Format: Wenwen Chien, Jinfen Xiao, Ling-Wen Ding, Muhammad Ikhsan B. Muzakar, Qiao-Yang Sun, Sigal Gery, William Senapedis, Sharon Shacham, Erkan Baloglu, H. Phillip Koeffler. Novel PAK4 allosteric modulators (PAMs) provide potential therapeutic options in human gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 138. doi:10.1158/1538-7445.AM2015-138
Abstract 1386: KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF1α accumulation
Authors: Ci Xinpei , Xing Changsheng , Zhang Baotong , Zhang Zhiqian , Ni Jenny Jianping , Zhou Wei , Dong Jin-Tang 
Published: August 2015

Abstract
Background: KLF5 is a basic transcriptional factor that regulates multiple physiopathological processes. Our recent study showed that deletion of Klf5 in mouse prostates promotes tumorigenesis initiated by the deletion of Pten. While molecular characterization of Klf5-null tumors suggested that angiogenesis was partially responsible for tumor promotion, the precise function and mechanism of KLF5 deletion in prostate tumor angiogenesis remain unclear.
Results: Using histological staining of Pten-null mouse prostates, we observed that deletion of Klf5 significantly increased the number of microvessels, which was accompanied by the upregulation of multiple angiogenesis-related genes based on microarray analysis with MetaCore software. In human umbilical vein endothelial cells (HuVECs), tube formation and migration, both of which are indicators of angiogenic activities, were decreased by conditioned media from PC-3 and DU 145 human prostate cancer cells with KLF5 overexpression, but increased by media from cells with KLF5 knockdown. HIF1α, a key angiogenesis inducer, was upregulated by KLF5 loss at the protein but not the mRNA level in both mouse tissues and human cell lines, as examined by immunohistochemical staining, real-time RT-PCR and Western blotting. Consistently, KLF5 loss also upregulated VEGF and PDGF, two pro-angiogenic mediators of HIF1α function, as analyzed by immunohistochemical staining in mouse tissues and ELISA in conditioned media. Mechanistically, AKT activity, which caused the accumulation of HIF1α, was increased by KLF5 knockout or knockdown but decreased by KLF5 overexpression. Consistently, PI3K/AKT inhibitors abolished the effects of KLF5 knockdown on angiogenic activity, HIF1α accumulation, and VEGF and PDGF expression.
Conclusion: KLF5 loss enhances tumor angiogenesis by attenuating PI3K/AKT signaling and subsequent accumulation of HIF1α in PTEN deficient prostate tumors.
Citation Format: Xinpei Ci, Changsheng Xing, Baotong Zhang, Zhiqian Zhang, Jenny Jianping Ni, Wei Zhou, Jin-Tang Dong. KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF1α accumulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1386. doi:10.1158/1538-7445.AM2015-1386
Abstract 1400: Evaluation of tumor-initiating cell populations in the KPC mouse model of pancreatic cancer
Authors: Dosch Joseph S. , Ziemke Elizabeth K. , Shettigar Amrith , Rehemtulla Alnawaz , Sebolt-Leopold Judith S. 
Published: August 2015

Abstract
There continue to be many questions about the frequency and phenotype of tumor-initiating cells or cancer stem cells (CSCs) which may play an important role in cancer metastasis and drug resistance in several tumor types, including pancreatic cancer. The KrasG12D, Trp53R172H, and Pdx-1-Cre (KPC) induced model of pancreatic cancer has gained considerable attention for its ability to replicate the clinical features of the disease. Here, we report the generation of a novel syngeneic xenograft model of luciferase-tagged pancreatic tumor cells (KPCL) to facilitate the investigation of the tumorigenic capacity of this cancer model. Limiting dilution analysis of bulk KPCL tumor cells revealed that 1/87 cells were capable of forming new tumors, a number considerably higher than reported for human pancreatic adenocarcinomas. Cell surface markers CD44, CD24, CD133, c-Met, and functional ALDEFLUOR activity, previously shown to mark CSC populations in human and mouse pancreatic tumors, were heterogeneous across a large panel of spontaneous KPCL tumors. Additional testing of CD133 and ALDEFLUOR populations were unable to enrich for tumorigenic populations when transplanted into syngeneic mice. Additionally, spheroid cultures initiated from KPCL tumors did not enrich for cells with stem-like characteristics and were not significantly more tumorigenic than KPCL cells cultured as monolayers. These studies demonstrate that the tumor-forming potential of KPC cells is common, and may not fit the hierarchically organized CSC model that is reported for the human disease.
Citation Format: Joseph S. Dosch, Elizabeth K. Ziemke, Amrith Shettigar, Alnawaz Rehemtulla, Judith S. Sebolt-Leopold. Evaluation of tumor-initiating cell populations in the KPC mouse model of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1400. doi:10.1158/1538-7445.AM2015-1400
Abstract 1408: Generation of 3D-microtissues suitable for drug screening with lentivirally GFP-labelled CD44+CD24- breast cancer cells enriched by irradiation
Authors: Höfig Ines , Rosemann Michael , Albrecht Michaela , Ingawale Yashodhara , Kelm Jens M. , Atkinson Michael J. , Thirion Christian , Anastasov Natasa 
Published: August 2015

Abstract
A stem cell like subpopulation of human T47D and MDA-MB-361 breast cancer cells (CD44+CD24-) was enriched by irradiation (2 Gy) and isolated using magnetic activated cell sorting. As an additional stem cell model, primary murine mesenchymal stem cells (MSCs) were isolated from the bone marrow of C3HxBL mice. We confirmed the stemness phenotype by repopulating heterogeneous cancer cell lines from isolated CD44+CD24- cells or by inducing differentiation of MSCs to the osteocyte, adipocyte and chondrocyte lineage.
For gene delivery in cancer research, lentiviral transduction protocols are widely used though low transduction efficiencies of especially primary cells force the use of high lentiviral titers. In search for an optimized transduction protocol we came across a poloxamer-based chemical adjuvant to increase lentiviral gene delivery in primary cells [Höfig et al, Journal of Gene Medicine, 2012 and Höfig et al, Biomaterials, 2014]. Next we aimed to expand these benefits to transduce cells with a stem cell phenotype. After lentiviral transduction of a GFP encoding lentivirus in the presence of the poloxamer-based chemical adjuvant we could detect highest numbers of GFP expressing cells. Neither the chemical adjuvant nor the transgenic GFP expression altered the stemness phenotype of those cells analysed by repopulation or differentiation assays and by detection of stem cell markers on mRNA level (CD133 and Sox2). To monitor the fate of GFP-expressing CD44+CD24- cells, we cultured them in 3D-microtissues in mix with unlabelled bulk cells and analysed the effect of irradiation on cell number and location of CD44+CD24- cells within the spheroid.
In this study we present a method for induction and isolation of human breast cancer cells with a stem cell like phenotype and developed an improved lentiviral transduction method by a chemical adjuvant preserving the stemness character in human and murine cells. Efficient lentiviral transduction enabled the generation of 3D-microtissues with GFP-labeled CD44+CD24- cells that both can be studied in cancer research and shall have applications for drug screening.
Citation Format: Ines Höfig, Michael Rosemann, Michaela Albrecht, Yashodhara Ingawale, Jens M. Kelm, Michael J. Atkinson, Christian Thirion, Natasa Anastasov. Generation of 3D-microtissues suitable for drug screening with lentivirally GFP-labelled CD44+CD24- breast cancer cells enriched by irradiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1408. doi:10.1158/1538-7445.AM2015-1408
Abstract 1436: The SxxSS motif of T-cell Factor-4 isoforms regulates Wnt5a expression and EMT in human liver cancer cells
Authors: Koga Hironori , Nakamura Toru , Abe Mitsuhiko , Ikezono Yu , Wada Fumitaka , Yano Hirohisa , Torimura Takuji 
Published: August 2015

Abstract
Background: The T-cell factor (TCF)-4 is a key transcriptional protein activated by Wnt/β-catenin signaling. Previously we identified 14 TCF-4 isoforms derived from human HCC cell lines (Exp Cell Res 2011). The TCF-4J and K pair have been characterized based on the presence (K) or absence (J) of a SxxSS motif. TCF-4J-overexpressing HCC cells (J cells) exhibited high tumorigenic potential in contrast to TCF-4K-overexpressing cells (K cells) (PLoS ONE 2012). However, K cells often showed morphological alteration, reminiscent of epithelial-mesenchymal transition (EMT), which is involved in non-canonical Wnt signaling (BMC Cancer 2013). The finding suggested that the SxxSS motif had potential to regulate EMT through the non-canonical Wnt signaling pathway. Thus, the AIM of this study was to investigate whether the SxxSS motif modulated expression levels of EMT regulators and Wnt5a, a representative non-canonical Wnt ligand. Methods: The human HCC cell line HAK-1A (Hepatology 1993) was used. TCF-4K mutants (269A, 272A, and 273A) were prepared with conversion of serine (S) in the SxxSS motif to alanine (A) by site-directed mutagenesis. HAK-1A-derived stable clones overexpressing TCF-4J, K, and K-mutants (269A, 272A, and 273A cells, respectively) were established. Western blot analysis and real-time RT-PCR were employed to evaluate protein and mRNA expression levels, respectively. Sh-RNA was used to knockdown wnt5a gene expression. Results: The 269A-mutant cells robustly expressed Wnt5a in both protein and mRNA levels, while empty vector-transfected cells (control), J cells, or K cells did not. Of note, Wnt5a expression was coupled with SLUG expression and EMT-like cellular morphological change. Snail was hardly expressed in the cells examined in this study. When the Wnt5a expression was specifically silenced by using sh-RNA, the expression level of SLUG was clearly decreased. Conclusion: The findings in this study suggest that serine 269 (the first serine) of the SxxSS motif of TCF-4 is a major switch to control Wnt5a transcription, thereby modulating the expression level of the EMT-regulator SLUG in a human HCC cell line.
Citation Format: Hironori Koga, Toru Nakamura, Mitsuhiko Abe, Yu Ikezono, Fumitaka Wada, Hirohisa Yano, Takuji Torimura. The SxxSS motif of T-cell Factor-4 isoforms regulates Wnt5a expression and EMT in human liver cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1436. doi:10.1158/1538-7445.AM2015-1436
Abstract 1442: Understanding the role of autophagy during cancer metastasis
Authors: Lim Maegan M. , Teo Ziqiang , Choo Chee Chong , Zhu Pengcheng , Tan Nguan Soon 
Published: August 2015

Abstract
Introduction:
Autophagy is a catabolic process that involves the lysosomal degradation and recycling of cellular components. It acts as a cell protective mechanism to promote cellular homeostasis or survival during nutrient deprivation. Studies in the past decade have shown the involvement of autophagy during tumorigenesis, but much are left to be debated on its controversial role as a tumour suppressor or a potential protective role in promoting cancer cell survival. Knockout of autophagic core machinery proteins in mice models showed increase potential of tumorigenic development. Recent findings also suggested that autophagy plays a part during cancer cell metastasis, but till date, there is no significant evidence to clearly define the involvement of autophagy and the mechanistic behind it. Our study involves defining the role of autophagy during metastasis and the molecular drivers behind the process.
Material & Methods:
Using human squamous cell carcinoma cell lines, we induce epithelial-mesenchymal transition (EMT) with three different methods to study the change in the autophagy level during the process.
Results:
Our unpublished data have demonstrated a higher autophagy level during our three models of EMT induction. Guided by the microarray data, we investigated the molecular drivers behind the change in autophagy levels and showed evidence that knocking down of certain molecular drivers reverses the effect and delay EMT.
Citation Format: Maegan M. Lim, Ziqiang Teo, Chee Chong Choo, Pengcheng Zhu, Nguan Soon Tan. Understanding the role of autophagy during cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1442. doi:10.1158/1538-7445.AM2015-1442
Abstract 1446: Induction of epithelial-to-mesenchymal transition (EMT) by SL-15 knockdown contributes to anoikis resistance in human colorectal cancer metastases
Authors: Jun Soo Young , Cho Hyun-Soo , Lee Jeong-Ju , Ahn Jun-Ho , Yoon Ji-Yong , Lee Jae-Hye , Choi Min Hyuk , Kim Nam-Soon 
Published: August 2015

Abstract
Purpose of the study: Metastasis or systemic dissemination of cancer cells into secondary organs is responsible for 90% of cancer-related fatalities. Our team previously screened out SL-15 as therapeutic target of gastric cancer through the analysis of gene expression profiling. In this study, we investigated the roles of human SL-15 in colorectal cancer (CRC) metastasis. Experimental procedures: SL-15 levels of metastatic liver CRC tissues and of primary CRC tissues as well as of adjacent nontumour tissues were compared using quantitative RT-PCR. Transwell and wound healing methods were used to determine the migration/invasion abilities of CRC cells. Flow cytometery analysis was performed to measure the apoptotic ratio as well as the levels of E-cadherin/p53/SL-15. Confocal observation and Western blot analysis were used for studying the underlying mechanisms of small interfering RNA against SL-15 (siSL-15)-induced CRC metastasis. Results: The level of SL-15 was higher in the order of metastatic liver CRC tissues, primary CRC tissues and then the adjacent nontumor tissues. siSL-15 significantly induced the migration/invasion of CRC cells that was almost entirely suppressed by the co-expression of SL-15. Importantly, the application of siSL-15 contributes to anoikis resistance of CRC cells via the upregulation of zinc finger E-box-binding homeobox 1 (ZEB1) in stem-like subtype CRC cells and intestinal trefoil factor (ITF) in goblet- like subtype CRC cells by the inhibition of glycogen synthase kinase 3 β (GSK3β) and of β-catenin degradation, thereby leading to downregulation of E-cadherin as well as p53 degradation. Importantly, the interactions among SL-15/p53/GSK3β that were dissociated upon the application of siSL-15 were determined. Conclusions: SL-15 is more highly up-regulated in metastatic liver CRC cancer than in primary CRC cancer and the adjacent nontumor tissue: SL-15 knockdown contributes to anoikis resistance of CRC cells and CRC metastasis via inducing epithelial-to-mesenchymal transition as well as p53 degradation due to the dissociation of SL-15 with GSK3β and p53.
Citation Format: Soo Young Jun, Hyun-Soo Cho, Jeong-Ju Lee, Jun-Ho Ahn, Ji-Yong Yoon, Jae-Hye Lee, Min Hyuk Choi, Nam-Soon Kim. Induction of epithelial-to-mesenchymal transition (EMT) by SL-15 knockdown contributes to anoikis resistance in human colorectal cancer metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1446. doi:10.1158/1538-7445.AM2015-1446
Abstract 145: HOTTIP, an oncogenic long non-coding RNA, is frequently up-regulated in hepatocellular carcinoma and is negatively regulated by tumor suppressive microRNA miR-125b
Authors: Tsang Felice H. , Au Sandy L. , Wei Lai , Fan Dorothy N. , Lee Joyce M. , Wong Carmen C. , Ng Irene O. , Wong Chun-Ming 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is one of the most common human cancers. Due to the lack of early diagnostic and effective treatment modalities, the mortality of HCC is high. The development and progression of HCC is a multistep process driven by the accumulation of genetic and epigenetic alterations. Recently, emerging evidence has suggested the role of long non-coding RNAs (lncRNAs) in human carcinogenesis. Herein, by profiling the expression of 88 well-annotated lncRNAs, we identified that HOTTIP was the most significantly up-regulated lncRNA (81%, 57/70) in human HCCs, even in early stage of HCC formation. Functionally, knockdown of HOTTIP attenuated HCC cell proliferation in vitro and markedly abrogated tumorigenicity in vivo. In addition, knockdown of HOTTIP also inhibited migratory ability of HCC cells and significantly abrogated lung metastasis in orthotopic implantation model in nude mice. HOTTIP is an antisense lncRNA mapped to the distal end of the HOXA gene cluster. Knockdown of HOTTIP significantly suppressed the expression of a number of HOXA genes. Furthermore, we identified miR-125b as a post-transcriptional regulator of HOTTIP. Ectopic expression of miR-125b abolished HOTTIP-coupled luciferase activity and suppressed the endogenous level of HOTTIP. Moreover, in human HCCs, HOTTIP expression negatively correlated with that of miR-125b. In Summary, our findings suggest that HOTTIP is a novel oncogenic lncRNA, with miR-125b being its negative regulator. It contributes to hepatocarcinogenesis by regulating the expression of its neighboring protein-coding genes.
Citation Format: Felice H. Tsang, Sandy L. Au, Lai Wei, Dorothy N. Fan, Joyce M. Lee, Carmen C. Wong, Irene O. Ng, Chun-Ming Wong. HOTTIP, an oncogenic long non-coding RNA, is frequently up-regulated in hepatocellular carcinoma and is negatively regulated by tumor suppressive microRNA miR-125b. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 145. doi:10.1158/1538-7445.AM2015-145
Abstract 1466: Patient-derived xenograft models for pancreatic adenocarcinoma demonstrate retention of tumor morphology through the incorporation of murine stromal elements
Authors: Delitto Daniel , Pham Kien , Vlada Adrian C. , Sarosi George A. , Thomas Ryan M. , Behrns Kevin E. , Liu Chen , Hughes Steven J. , Wallet Shannon M. , Trevino Jose G. 
Published: August 2015

Abstract
Direct implantation of viable surgical specimens provides a representative preclinical platform in pancreatic adenocarcinoma (PC). Patient-derived xenografts consistently demonstrate retained tumor morphology and genetic stability. However, the evolution of the tumor microenvironment over time remains poorly characterized in these models. This work specifically addresses the recruitment and incorporation of murine stromal elements into expanding patient-derived PC xenografts, establishing the rapidity by which murine cells are integrated into networks of invading cancer cells. In addition, we provide methodology and observations in the establishment and maintenance of a patient-derived PC xenograft model. A total of 25 histologically confirmed pancreatic adenocarcinoma specimens were implanted subcutaneously into NOD-SCID mice. Patient demographics, staging, pathologic analysis and outcomes were analyzed. After successful engraftment of tumors, histologic and immunofluorescent analyses were performed on explanted tumors. PC specimens were successfully engrafted in 15 of 25 (60%) of attempts. Successful engraftment does not appear to correlate with clinicopathologic factors or patient survival. Tumor morphology is conserved through multiple passages and tumors retain metastatic potential. Interestingly, despite morphologic similarity between passages, human stromal elements do not appear to expand with invading cancer cells. Rather, desmoplastic murine stroma dominates the xenograft microenvironment after the initial implantation. Recruitment of stromal elements in this manner to support and maintain tumor growth represents a novel avenue for investigation into tumor-stromal interactions.
Citation Format: Daniel Delitto, Kien Pham, Adrian C. Vlada, George A. Sarosi, Ryan M. Thomas, Kevin E. Behrns, Chen Liu, Steven J. Hughes, Shannon M. Wallet, Jose G. Trevino. Patient-derived xenograft models for pancreatic adenocarcinoma demonstrate retention of tumor morphology through the incorporation of murine stromal elements. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1466. doi:10.1158/1538-7445.AM2015-1466