bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-272: AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells.
Authors: Asiedu Michael K. , Beauchamp-Perez Francis , Ingle James N. , Behrens Marshall D. , Radisky Derek C. , Knutson Keith 
Published: August 2014

Abstract
Despite significant progress in the treatment of breast cancer particularly through the use of targeted therapy, relapse and chemo-resistance remain a major hindrance in the fight to minimize the burden of the disease. Accumulating evidence suggest that breast cancer stem cells (BCSCs), which show resistance to chemotherapy and radiation, drive tumor initiation and disease recurrence. It is becoming increasingly clear that a rare subpopulation of cells known as cancer stem cells (CSC), able to be generated through epithelial to mesenchymal transition (EMT) and capable of tumor initiation and self-renewal, contributes to treatment resistance and metastases. This means that a more effective therapy should target both the chemoresistant CSCs and the proliferating epithelial cells that give rise to them in order to reverse EMT and attenuate their conversion to CSCs. Here, we demonstrate a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism and regulate breast CSC (BCSC) self-renewal and chemoresistance. Downregulation of AXL expression using AXL inhibitor MP470 (amuvatinib) or shRNA reversed EMT in mesenchymal normal human mammary epithelial cells and murine BCSCs attenuating self-renewal and restored chemosensitivity of the BCSCs. AXL expression was also found to be associated with expression of stem cell genes, regulation of metastases genes, increased tumorigenicity, and was important for BCSC invasion and migration. Inactivation of AXL also led to downregulation of NFκB pathway and reduced tumor formation in vivo. Together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anti-cancer therapies and to reduce breast cancer recurrence and metastases.
Citation Format: Michael K. Asiedu, Francis Beauchamp-Perez, James N. Ingle, Marshall D. Behrens, Derek C. Radisky, Keith Knutson. AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem 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 LB-272. doi:10.1158/1538-7445.AM2013-LB-272
Abstract LB-276: CLCA2 interactor EVA1 maintains epithelial differentiation of HMEC.
Authors: Elble Randolph C. , Ramena Grace , Walia Vijay 
Published: August 2014

Abstract
CLCA2 is a p53-inducible transmembrane protein that is frequently downregulated in breast cancer. It is induced during MET in immortalized HMEC, and its knockdown causes EMT. To determine how CLCA2 promotes epithelial differentiation, we searched for interactors using membrane dihybrid screening. We discovered a strong interaction with the cell junctional protein EVA1 (Epithelial V-like Antigen 1), confirmed by co-immunoprecipitation and immunolocalization experiments. Like CLCA2, EVA1 is a type I transmembrane protein that is regulated by p53. It mediates homophilic cell-cell adhesion in diverse epithelial tissues. We found that EVA1 is frequently downregulated in breast tumors and breast cancer cell lines, especially those of mesenchymal phenotype. Like CLCA2, knockdown of EVA1 resulted in rapid EMT in immortalized HMEC and increased invasiveness. The interacting domains were delimited by deletion analysis, revealing that the CLCA2 transmembrane segment (TMS) alone was sufficient for the interaction with EVA1. Surprisingly, EVA1 bound to the TMS only in the context of full length CLCA2 precursor, but not in the context of the C-terminal cleavage product, suggesting that cleavage of CLCA2 causes a conformational shift and release of EVA1. The interaction was specific, as other transmembrane proteins did not interact with CLCA2 or EVA1. To determine whether CLCA2 regulates EVA1 localization to tight junctions or hemophilic ligation, we fused the CLCA2 or EVA1 TMS to a secreted heterologous protein to create competitive inhibitors. These results identify the CLCA2-EVA1 complex as pivotal in maintaining epithelial differentiation and explain the downregulation of both genes during tumor progression.
Citation Format: Randolph C. Elble, Grace Ramena, Vijay Walia. CLCA2 interactor EVA1 maintains epithelial differentiation of HMEC. [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 LB-276. doi:10.1158/1538-7445.AM2013-LB-276
Abstract LB-282: Loss of PTP-PEST promotes tumor invasion, apoptosis resistance and activation of STAT3 in metastatic colon cancer.
Authors: Espejo Rosario , Jeng Yowjiun , Johnson Camille , Carmical Russ , Brasier Allan , Chao Celia , Sastry Sarita K. 
Published: August 2014

Abstract
The transcription factor STAT3 is hyperactivated by phosphorylation on Y705 in over 75% of metastatic colon cancers and is associated with EMT, cancer stem cells, survival and chemoresistance. However, the mechanisms of STAT3 inactivation are not well-defined. Here, we identified the protein tyrosine phosphatase, PTP-PEST, as a novel negative regulator of STAT3 in colon carcinoma cells. Using lentiviral-mediated shRNA silencing of PTP-PEST in HCT116 colon carcinoma cells, we show that PTP-PEST knockdown enhances activation of STAT3. Whereas STAT3 is activated by cell attachment to collagen in control cells expressing non-targeting shRNA, PTP-PEST knockdown leads to constitutive, anchorage-independent STAT3 activity. Silencing of PTP-PEST enhances anchorage-independent survival in soft agar, tumor sphere growth and matrigel invasion in vitro. Consistent with increased invasion and survival, PTP-PEST knockdown cells showed enhanced expression of STAT3 target genes, MMP2 and mcl-1. Significantly, PTP-PEST knockdown enhanced apoptosis resistance in three-dimensional matrigel cultures in response to the chemotherapy drug, 5-fluorouracil (5-FU). PTP-PEST knockdown cells treated with 5-FU in 3-D matrigel spheroid cultures showed increased cell viability, reduced caspase-3 activation and enhanced activation of STAT3 relative to non-targeting controls. Furthermore, in subcutaneous nude mouse xenografts, although overall tumor growth was not affected by PTP-PEST knockdown, immunohistochemistry showed reduced caspase-3 and elevated P-STAT3 levels in these tumors. Intrasplenic injection of PTP-PEST knockdown cells in athymic nude mice resulted in enhanced metastatic potential as assessed by quantitative PCR for human DNA content in mouse liver. Finally, reduced PTP-PEST expression correlates with metastasis in clinical specimens from colon cancer patients. Taken together, these findings suggest that down-regulation of PTP-PEST in colon cancer may promote metastasis through increased invasion and apoptosis resistance, mediated, in part, by enhanced activation of STAT3.
Citation Format: Rosario Espejo, Yowjiun Jeng, Camille Johnson, Russ Carmical, Allan Brasier, Celia Chao, Sarita K. Sastry. Loss of PTP-PEST promotes tumor invasion, apoptosis resistance and activation of STAT3 in metastatic 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 LB-282. doi:10.1158/1538-7445.AM2013-LB-282
Abstract LB-284: Bone marrow-derived progenitor cells develop into myeloid-derived suppressor cells at metastatic sites.
Authors: Giles Amber , Vicioso Yorleny , Persenaire Christianne , Kasai Miki , Highfill Steven , Mendoza Arnulfo , Kaplan Rosandra 
Published: August 2014

Abstract
The ability of tumor cells to metastasize to distant tissues is the most lethal aspect of cancer. Prior to detectable metastasis tumors elicit distant changes within the bone marrow and future sites of metastasis, including formation of the pre-metastatic niche. We have found that prior to detectable spontaneous metastasis, a primary tumor causes enhanced production and mobilization of progenitor cells from the bone marrow into the blood. We find in cancer patients that increased circulating progenitors are associated with metastatic disease progression. By utilizing bone marrow transplant models and a novel ex vivo lung culture, we demonstrate that bone marrow-derived progenitor cells accumulate at the primary tumor as well as metastatic lesions. As our cancer models approach detectable spontaneous metastases, we observe a loss of progenitor cells in pre-metastatic sites and an increase in myeloid-derived suppressor cells (MDSCs). We further traced adoptively transferred bone marrow-derived progenitors in tumor-bearing mice and demonstrate that these cells contribute to the MDSC population. Together, these data suggest that circulating progenitor cells provide a prognostic tool to predict metastatic dissemination. Furthermore, these cells likely contribute to metastatic progression by developing into MDSCs within the primary tumor and at metastatic sites.
Citation Format: Amber Giles, Yorleny Vicioso, Christianne Persenaire, Miki Kasai, Steven Highfill, Arnulfo Mendoza, Rosandra Kaplan. Bone marrow-derived progenitor cells develop into myeloid-derived suppressor cells at metastatic sites. [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 LB-284. doi:10.1158/1538-7445.AM2013-LB-284
Abstract LB-306: A novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo.
Authors: Reebye Vikash 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) occurs predominantly in patients with liver cirrhosis. Therapies to simultaneously reduce tumour burden and improve liver function are limited. Here, we show an innovative RNA-based targeted approach to enhance endogenous albumin production whilst reducing liver tumour burden.
We designed short activating RNA (saRNA) oligonucleotides to enhance expression of the transcriptional regulator and activator of albumin gene expression, CCAAT/enhancer-binding protein-α (C/EBPα). Increased levels of both C/EBPα and albumin mRNA in addition to a 3-fold increase in albumin secretion and a 50% decrease in cell proliferation were observed in saRNA transfected hepatocellular carcinoma cells (HepG2).
Intravenous injection of C/EPBα-saRNA in a liver cirrhotic rat model with multifocal liver tumours caused a significant increase in circulating serum albumin levels, and reduction in circulating ALT and AST levels- suggesting an amelioration of liver function. Concomitantly a significant reduction in tumour burden and pre-neoplastic transformation placental glutathione S-transferase (GST-p) staining was observed.
Using mRNA expression microarray, quantitative PCR, Western blot and methylation analysis of CpG islands in C/EPBα-saRNA transfected HepG2 cells, we found up-regulation of C/EBPα and albumin; and a negative regulation of IL6R, c-Myc and STAT3 phosphorylation.
We demonstrate for the first time that a novel injectable saRNA oligonucleotide successfully reduces tumour burden and simultaneously improves liver function in a clinically relevant liver cirrhosis/HCC model.
Citation Format: Vikash Reebye. A novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. [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 LB-306. doi:10.1158/1538-7445.AM2013-LB-306
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract LB-313: Development of a novel anti-MYC therapeutic with efficacy against liver and kidney cancers.
Authors: Bellovin David I. , Yevtodiyenko Aleksey , Adam Stacey J. , Fernando Hanan , Arzeno Julia , Gabay Meital , Felsher Dean W. 
Published: August 2014

Abstract
One of the most attractive, yet elusive, targets for cancer therapy is the MYC oncogene. MYC is overexpressed in the majority of human cancers, and we and others have shown that suppression of this oncogene is sufficient to induce sustained tumor regression, a phenomenon known as oncogene addiction. However, no viable therapy has been developed as yet that targets this crucial regulator of the tumor phenotype. Here, we report the development of a novel antisense therapeutic that targets the MYC oncogene. This inhibitor can potently suppress MYC expression in primary tumors in vivo, as demonstrated by immunohistochemistry and real-time PCR. Importantly, we show that treatment with the anti-MYC drug significant reduces tumor onset and progression in transgenic mouse models of primary hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) cancer. We imaged tumor growth via MRI and utilized quantitative image analysis to demonstrate the inhibition of HCC and RCC progression, confirming our results on total tumor burden histologically after four weeks of drug treatment. Additionally, this antisense therapy against MYC can also attenuate the growth of human HCC cells in vivo, irrespective of the inducing oncogene. In contrast with other reported MYC inhibitors, our approach results in no discernible toxicity due to MYC suppression on any organs examined in the treated animals. Thus, we have established a novel therapy that directly inhibits the MYC oncogene, representing a potentially exciting advance in the field of targeted cancer therapeutics.
Citation Format: David I. Bellovin, Aleksey Yevtodiyenko, Stacey J. Adam, Hanan Fernando, Julia Arzeno, Meital Gabay, Dean W. Felsher. Development of a novel anti-MYC therapeutic with efficacy against liver and kidney cancers. [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 LB-313. doi:10.1158/1538-7445.AM2013-LB-313
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract LB-318: Reshaping the cancer proteome: therapeutic targeting of signaling and resistance in cancer by antisense manipulation of RNA processing.
Authors: Cartegni Luca , Spraggon lee 
Published: August 2014

Abstract
Activation of the receptor tyrosine kinase (RTK) signaling pathways represents a key aspect of tumorigenesis in a broad range of human cancers. Thus, targeting of pathogenic RTKs, mainly with small molecule inhibitors and antibodies, has become an attractive therapeutic approach for cancer therapy. However, resistance by multiple mechanisms, including mutational re-activation of RTK signaling, activation of alternative RTK pathways, EMT transition and others, inevitably occurs over time.
We recently identified a number of novel secreted soluble decoy RTKs isoforms (sdRTKs) generated by a U1-snRNP-dependent alternative intronic polyadenylation mechanism. We therefore developed a novel antisense-based method to effectively activate the expression of these sdRTKs, both in vitro and in vivo. This leads to the generation of endogenous dominant negative variants of RTKs, which can specifically affect the signaling of pathogenic RTKs and therefore provides a novel cancer therapy approach.
Employing specific antisense compounds designed to activate intronic polyA sites, we are able to induce natural truncated EGFR variants that encode its extracellular ligand-binding domain but lack the intracellular signaling domain. These compounds thus can inhibit EGFR signaling by a three fold-mechanism: 1) removal of FL receptor, 2) sequestration of ligands and 3) non-productive dimerization with residual receptors. They are therefore designed to affect signaling both of targeted cells and of bystanders.
Here we will show that, using this approach, we can target EGFR signaling both in vitro and in tumors. Importantly, with this method we can bypass the emergence of resistance typically seen with targeted drug treatments. Further development of this methodology will therefore provide the basis for an exciting novel approach to targeting and inhibiting oncogenic EGFR signaling and other pathways in a variety of cancers.
Citation Format: Luca Cartegni, lee Spraggon. Reshaping the cancer proteome: therapeutic targeting of signaling and resistance in cancer by antisense manipulation of RNA processing. [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 LB-318. doi:10.1158/1538-7445.AM2013-LB-318
Abstract LB-321: Combination dendritic cell and conventional chemoradiation therapy improves survival for rectal cancer in a murine model.
Authors: Kachare Swapnil D. , Cayer Jennifer M. , Carver F. Melinda , Englert Zachary P. , Verbanac Kathryn M. , Zervos Emmanuel E. , Vohra Nasreen A. 
Published: August 2014

Abstract
The goal of neoadjuvant therapy in rectal cancer is to downstage or preferably eradicate the tumor prior to resection. Achieving complete pathologic response (CPR) using neoadjuvant chemoradiation is associated with improved overall and disease free survival. The aim of this study was to achieve improved complete pathologic response rates and survival by combining intra-tumoral injection of dendritic cells with conventional therapy. A syngeneic rectal cancer cell line (CT26) was subcutaneously injected into the thigh of immunocompetent Balb/c mice. Mice either received no treatment, conventional chemoradiation (CXRT) (5-fluorouracil + XRT) for 3 weeks, or CXRT plus tumor-lysate pulsed dendritic cells (CXRT/DC). Specific anti-CT26 cytotoxic T cell (CTL) activity was determined using standard chromium release assay. Flow cytometry for immune cell subsets was performed on cells isolated from spleens and tumors. Animals in the control group showed predictable uninhibited growth and all were euthanized due to tumor size. CXRT animals showed improved survival but none achieved complete response. Thirty three percent of the animals in CXRT/DC group exhibited CPR. Median survival for the control, CXRT, and CXRT/DC treated animals was 24, 46.5, 67 days, (p&lt;0.0001). Splenocytes from CXRT/DC treated mice exhibited higher specific anti-CT26 CTL activity (28%) when compared to CXRT (17%), untreated control (11%) and naïve mice (&lt;1%). Flow cytometry demonstrated an increase in regulatory T cells (Tregs), macrophages, granulocytic myeloid derived suppressor cells (MDSCs) and monocytic MDSCs in tumor bearing animals, (p&lt;0.05). Dendritic cell activity stimulates anti-tumor CTL responses, but may also decrease MDSC and Treg mediated immunosuppression. Addition of dendritic cells to conventional chemoradiation therapy for rectal cancer increases complete pathologic response and thereby survival via immune modulation. Further analysis will allow subset comparisons between treatment groups.
Citation Format: Swapnil D. Kachare, Jennifer M. Cayer, F. Melinda Carver, Zachary P. Englert, Kathryn M. Verbanac, Emmanuel E. Zervos, Nasreen A. Vohra. Combination dendritic cell and conventional chemoradiation therapy improves survival for rectal cancer in a murine model. [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 LB-321. doi:10.1158/1538-7445.AM2013-LB-321
Abstract LB-325: Sphingosine-1-phosphate links chronic intestinal inflammation to development of colitis-associated cancer.
Authors: Nagahashi Masayuki , Liang Jie , Kim Eugene Y. , Harikumar Kuzhuvelil B. , Yamada Akimitsu , Huang Wei-Ching , Hait Nitai C. , Allegood Jeremy C. , Price Megan M. , Avni Dorit , Takabe Kazuaki , Kordula Tomasz , Milstien Sheldon , Spiegel Sarah 
Published: August 2014

Abstract
Inflammatory bowel disease is an important risk factor for colorectal cancer. The pro-inflammatory cytokines TNF-alpha and IL-6 and their downstream master transcription factors NF-kappaB and Stat3 are critical regulators of chronic inflammation and cancer. There is growing evidence that sphingosine-1-phosphage (S1P), a pleiotropic bioactive sphingolipid metabolite formed inside cells by two closely related sphingosine kinases, SphK1 and SphK2, is involved in inflammation and cancer. In this work, we have shown that S1P produced by upregulation of SphK1 links chronic intestinal inflammation to CAC and both are exacerbated by deletion of SphK2. S1P is essential for production of the multifunctional NF-kappaB-regulated cytokine IL-6, persistent activation of the transcription factor Stat3, and consequent upregulation of the S1P receptor, S1PR1. Adoptive transfer demonstrated that SphK2 deficiency in hematopoietic cells contributed to colitis severity, IL-6 production, and activation of Stat3 and NF-kappaB. The pro-drug FTY720 decreased SphK1 and S1PR1 and eliminated the NF-kappaB-IL-6-Stat3 amplification cascade and development of CAC even in SphK2-/- mice, suggesting that FTY720 may be useful in treating colon cancer in individuals with ulcerative colitis. Thus, the SphK1-S1P-S1PR1 axis is at the nexus between NF-kappaB and Stat3 and connects chronic inflammation and CAC.
This work was supported by NIH grants R37GM043880, R01CA61774 (to S.S.) and K12HD055881 and the Susan G. Komen for the Cure Research Foundation grant (to K.T.). M.N. is a Japan Society for the Promotion of Science Postdoctoral Fellow. E.Y.K. and J.C.A. were supported by NIH training grant T32HL094290.
Citation Format: Masayuki Nagahashi, Jie Liang, Eugene Y. Kim, Kuzhuvelil B. Harikumar, Akimitsu Yamada, Wei-Ching Huang, Nitai C. Hait, Jeremy C. Allegood, Megan M. Price, Dorit Avni, Kazuaki Takabe, Tomasz Kordula, Sheldon Milstien, Sarah Spiegel. Sphingosine-1-phosphate links chronic intestinal inflammation to development of colitis-associated 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 LB-325. doi:10.1158/1538-7445.AM2013-LB-325