bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3211: Heterogeneity of PPARβ/δ expression in colorectal tumor stroma
Authors: Tan Eddie Han Pin , Sng Ming Keat , Chan Jeremy Soon Kiat , Tan Nguan Soon 
Published: August 2015

Abstract
Background: The role of PPARβ/δ in colorectal cancer has been a hot topic for debate, with both tumor-promoting and anti-tumor roles been reported. Current studies on colorectal cancer have focused on either the whole intestine or on the major tissue type, the intestinal epithelium. In recent years, various studies have emphasized the pro-inflammatory and tumor promoting effects of tumor stroma in various cancers. However, the involvement of tumor stroma in adenocarcinoma development remains a largely unexplored realm of colorectal research. Hence, we hypothesized that PPARB/D expression in colorectal tumor stroma may play an important role in colorectal carcinogenesis.
Methods: In this study, we aimed to investigate the role of PPARβ/δ in the colorectal tumor stroma. To study the role of the tumor stroma in vivo, we have adopted a model organism approach involving adult APCmin mice and AOM/DSS-treated wild-type mice models. We collected intestinal adenocarcinomas from these mice and extracted tumor stroma using microscopy-directed laser capture micro-dissection. The collected stroma were recovered for mRNA and analyzed for gene expression levels using real-time PCR.
Results and conclusion: We observed contrasting trends in the PPARβ/δ mRNA expression, with elevated levels in stroma of APCmin adenocarcinoma but decreased in AOM/DSS-induced tumors. Our results to date demonstrate the heterogeneity of colorectal tumor stroma and provide an insight to the distinct differences between the two often co-studied murine models of colorectal carcinogenesis. We therefore plan to study if this trend is also observed in human colorectal tumor samples and in murine colorectal cancer models carrying stromal-specific deletion of PPARβ/δ expression.
Citation Format: Eddie Han Pin Tan, Ming Keat Sng, Jeremy Soon Kiat Chan, Nguan Soon Tan. Heterogeneity of PPARβ/δ expression in colorectal tumor stroma. [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 3211. doi:10.1158/1538-7445.AM2015-3211
Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche
Authors: Price Trevor T. , Lee Clara H. , Cheng Qing , Lyerly H. Kim , Fogler William E. , Magnani John L. , Sipkins Dorothy A. 
Published: August 2015

Abstract
Distant metastases are the major cause of death from breast cancer. In estrogen receptor positive (ER+) breast cancer (BC) in particular, metastatic relapse can occur years after initial treatment, suggesting that disseminated tumor cells have a prolonged dormant phase before becoming proliferative. A major site of early disease dissemination and metastatic relapse of ER+ BC is the bone, although the critical signals that allow circulating breast cancer cells (BCCs) to identify bone marrow (BM) vasculature, enter the tissue, and tether to the BM microenvironment (BMM) are little understood. Investigating these interactions of BCCs with the BMM, however, could enable us to target the key biologic determinants allowing safe harbor for metastases within bone. To address the features of breast tumors associated with late recurrence, but not confounded by variations in systemic treatment, we compiled breast tumor gene expression data from 4,767 patients and established a discovery cohort consisting of 743 lymph node-negative patients who did not receive systemic neoadjuvant or adjuvant therapy. Using this data set, we found that expression of E-selectin ligands and CXCR4 were significantly elevated in ER+ tumors that had late recurrences. Based on these observations, we used intravital fluorescence microscopy to study the precise functions of E-selectin ligands and CXCR4 (SDF-1 receptor) in tumor metastasis in in vivo xenograft models and found that these play distinct roles in ER+ BCC migration in the BMM. Using highly specific E-selectin (GMI-1271) and CXCR4 (AMD3100) inhibitors, we determined that E-selectin interactions were critical for BCC entry into bone, while CXCR4/SDF-1 interactions anchored BCCs to the BMM. CXCR4 inhibition led to significant mobilization of BC micrometastases from the BMM into the peripheral circulation. Moreover, we found that dormant and proliferating BCCs occupy distinct regions of the BMM, with dormant BCCs predominantly found in SDF-1 and E-selectin rich regions and thus highly susceptible to AMD3100 mobilization. These findings shed light on how dormant and proliferating BCCs interact with the BMM and suggest new interventions to break the foothold of dormant BC micrometastases in bone.
Citation Format: Trevor T. Price, Clara H. Lee, Qing Cheng, H. Kim Lyerly, William E. Fogler, John L. Magnani, Dorothy A. Sipkins. Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche. [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 3212. doi:10.1158/1538-7445.AM2015-3212
Abstract 3223: A true orthotopic ovarian cancer patient-derived xenograft (PDX) model
Authors: Cui Hongmei , He Yingyan , Krepler Clemens , Tanyi Janos , Morgan Mark A. , Burger Robert A. , Kim Sarah , Ko Emily , Ince Tan , Herlyn Meenhard , Simpkins Fiona 
Published: August 2015

Abstract
Introduction: Patient derived xenografts (PDXs) show promise as models to study cancer as they recapitulate the principle characteristics of the patients’ original tumor such as histology, mutational status, DNA copy number, gene expression patterns, and clinical behavior while remaining biologically stable through passaged in mice. We used an orthotopic model transplanting tumor directly to the fallopian tube/ovary in order to accurately study the native environment and the progression of the ovarian cancer (OVCA).
Experimental Design: Fresh OVCA tumor was transplanted orthotopically to the fallopian tube/ovary of NSG 5-8 week old mice. Tumor growth was followed over time. Tumors were evaluated by IHC. Alu II probe staining was performed to evaluate human stroma content. RPPA and targeted DNA sequencing are in-process. Drug studies are in progress. Primary tumor lines are being generated.
Results: To date, we have transplanted tumor from 18 primary, 2 interval, and 5 recurrent ovarian debulking surgeries using an orthotopic ovarian tumor transplant approach with an 85% success rate in generating tumors in mouse passage 1 (MP1). The median time for tumors to reach ∼2 cm is 3 months when tumors are then passaged again (MP2/MP3). We have generated 8 BRCA 1/2 deleterious mutation positive carrier PDXs. Alu staining of PDXs demonstrates human cells in the stroma. We have generated 8 primary tumor cell lines from original tumors/PDXs.
Conclusions: We conclude that although technically more challenging, the orthotopic transplantation technique is feasible in generating ovarian cancer PDXs that most closely resemble the natural environment for ovarian cancer progression.
Citation Format: Hongmei Cui, Yingyan He, Clemens Krepler, Janos Tanyi, Mark A. Morgan, Robert A. Burger, Sarah Kim, Emily Ko, Tan Ince, Meenhard Herlyn, Fiona Simpkins. A true orthotopic ovarian cancer patient-derived xenograft (PDX) model. [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 3223. doi:10.1158/1538-7445.AM2015-3223
Abstract 3235: Validation of anti-human PD1 and PD-L1 antibodies in MiXeno mouse models
Authors: Zhang Juan , Qiao Meng , Zhang Lan , Shi Qian 
Published: August 2015

Abstract
As evidenced by strong clinical data from antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death protein-1 (PD-1), and its ligand PD-L1, cancer immunotherapy is now a major breakthrough in cancer treatment. Meanwhile, new immunotherapeutic agents with various targets and mechanisms, as well as new drug combinations are under active preclinical development. However, reliable humanized animal models are of increasing importance as more programs are reaching the in vivo stage, where direct evaluation of therapeutics with anti-human targets are necessary. We have previously reported our efforts in generating mouse MiXeno models that harbor human immune cells by engrafting immuno-deficient mice with human PBMC (the MiXenoTM model) to evaluate anti-PD-L1 antibody. In the current study, we carried out extensive validation of these models in vivo by generating multiple cell line-derived MiXeno models and testing them with anti-human PD-1 or PD-L1 antibodies in different animal strains (NOD/SCID vs. NPG). Our studies demonstrated that MiXeno models can successfully reconstitute human T cells in mice to support the anti-tumor activity of the immuno-therapeutic agents. MiXeno model is simple and fast, and may become valuable tools for in vivo evaluation of immunotherapeutic agents.
Citation Format: Juan Zhang, Meng Qiao, Lan Zhang, Qian Shi. Validation of anti-human PD1 and PD-L1 antibodies in MiXeno mouse models. [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 3235. doi:10.1158/1538-7445.AM2015-3235
Abstract 3254: Promotion of colon cancer invasion and metastasis via activation of Notch-Dab1-Abl-RhoGEF protein Trio
Authors: Taketo Mark 
Published: August 2015

Abstract
We have recently identified a metastasis suppressor gene for colorectal cancer (CRC); AES/Aes which encodes an endogenous inhibitor of Notch signaling. When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here we show that one of the genes induced by Notch signaling in CRC is DAB1/Dab1. Genetic depletion of Dab1 suppresses cancer invasion and metastasis in the Notch signaling-activated mice. Dab1 is phosphorylated by Abl tyrosine kinase, which activates Abl reciprocally. Consistently, inhibition of Abl suppresses cancer invasion in mice. Furthermore, we show that one of the targets of Abl Tyr-kinase is Rac/Rho-GEF protein Trio, and that phosphorylation at its Tyr residue 2681 (pY2681) causes Rho activation in CRC cells. Its unphosphorylatable mutation Trio(Y2681F) reduces the RhoGEF activity, and inhibits invasion of CRC cells. Importantly, Trio(pY2681) correlates with significantly poorer prognosis of CRC patients after surgery. These results indicate that Trio(pY2681) is one of the downstream effects by Notch signaling activation in CRC, and can be a prognostic marker, helping determine the therapeutic modality of CRC patients.
Citation Format: Mark Taketo. Promotion of colon cancer invasion and metastasis via activation of Notch-Dab1-Abl-RhoGEF protein Trio. [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 3254. doi:10.1158/1538-7445.AM2015-3254
Abstract 3269: Ezrin binds to DEAD-box RNA helicase DDX3 and regulates its function and protein level
Authors: Celik Haydar , Sajwan Kamal P. , Pai Amrita V. , Marsh Ben J. , Saygideger Kont Yasemin , Rahim Said , Han Jenny , Minas Tsion , Toretsky Jeffrey A. , Uren Aykut 
Published: August 2015

Abstract
Ezrin is a member of the ezrin-radixin-moesin (ERM) family of actin-membrane linker proteins that play key roles in regulating cell shape, movement, adhesion and signal transduction pathways. The expression of ezrin is linked to the metastatic progression in several cancers including osteosarcoma (OS). We discovered a small molecule, NSC305787, that inhibits ezrin activity and metastatic phenotype both in vitro and in vivo. We hypothesized that the anti-metastatic effects of NSC308787 could be mediated through preventing specific protein-protein interactions involving ezrin. In this study, we used affinity pull-down coupled with mass spectrometry-based proteomic approach to unravel putative ezrin interactors that are competed away by NSC305787. We identified a number of candidate ezrin binding proteins that are associated with metastatic behavior and implicated in the regulation of stress granule dynamics and protein translation initiation. We selected DDX3, a DEAD-box RNA helicase, as a candidate for further analysis. We confirmed that ezrin directly binds to DDX3. Depletion of ezrin protein expression by RNA interference in several cancer cell lines resulted in substantial reduction in DDX3 protein levels without affecting its transcription, which suggested that ezrin is required for post-transcriptional maintenance of DDX3 in the cell. Paradoxically, recombinant ezrin specifically inhibited the RNA duplex unwinding activity and stimulated the ATPase activity of DDX3. Our data suggest that ezrin regulates the translation of mRNAs with 5′ secondary structure through DDX3, at least in part, through maintaining its intracellular protein level and/or modulating its unwinding and ATPase activities. Therefore, our findings suggest that a novel function of ezrin regarding the regulation of mRNA translation exists that is independent from its classical role as a cytoskeletal cross-linker protein at the plasma membrane.
Citation Format: Haydar Celik, Kamal P. Sajwan, Amrita V. Pai, Ben J. Marsh, Yasemin Saygideger Kont, Said Rahim, Jenny Han, Tsion Minas, Jeffrey A. Toretsky, Aykut Uren. Ezrin binds to DEAD-box RNA helicase DDX3 and regulates its function and protein level. [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 3269. doi:10.1158/1538-7445.AM2015-3269
Abstract 327: 3D dynamics of the response to cell cycle checkpoint targeting drugs in multicellular tumour spheroids
Authors: LOBJOIS Valérie , MONDESERT Odile , FRONGIA Céline , DESMAISON Annaick , GOMES Aurélie , CAZALES Martine , Ducommun Bernard 
Published: August 2015

Abstract
Major recent advances have recently been made in the understanding of the molecular pathways regulating the cell cycle machinery and their deregulations in cancer. These results open new avenues for the development of innovative antitumor pharmacological strategies targeting the cell cycle and its checkpoints.
MultiCellular Tumor Spheroid (MCTS) are now considered as invaluable models to study cancer cell biology and for the preclinical development of new antiproliferative drugs.
To fully exploit the features of MCTS, it is essential to preserve the 3D regionalization level of analysis when investigating the effect of a drug. We will report here a breakthrough in the use of MCTS with new technological developments that can be used to explore the regionalization and the live dynamics of the effects of anticancer drugs in 3D.
Spheroids expressing fluorescent cell cycle reporters (i.e. Fucci) and biosensors were engineered and used to monitor cell cycle arrest and DNA damage Response (DDR) pathway activation induced by chemotherapeutic agents. The kinetics and regionalized aspects of the response were investigated on genetically modified spheroids using innovative 3D imaging strategy (based on 3D light sheet microscopy).
We will present our latest results on the characterization of the effects of several anticancer drugs including DNA damaging agents alone or in association with checkpoint abrogating compounds.
This study opens new perspectives for original 3D assays dedicated to the identification of new original targets and compounds and for the investigation of the dynamics of the 3D response to novel antiproliferative agents.
Citation Format: Valérie LOBJOIS, Odile MONDESERT, Céline FRONGIA, Annaick DESMAISON, Aurélie GOMES, Martine CAZALES, Bernard Ducommun. 3D dynamics of the response to cell cycle checkpoint targeting drugs in multicellular tumour spheroids. [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 327. doi:10.1158/1538-7445.AM2015-327
Abstract 3279: Expression of chemerin and chemerin receptors in neuroblastoma: implications in tumorigenesis
Authors: Tuemmler Conny , Snapkov Igor , Moens Ugo L. , Kogner Per , Johnsen John Inge , Sveinbjørnsson Baldur 
Published: August 2015

Abstract
Chemerin is an adipokine and immunomodulating factor that promotes chemotaxis of immature dendritic cells, natural killer cells, macrophages and endothelial cells. Secreted as prochemerin with low activity, it can be C-terminally processed by different proteases expressed by a broad range of cell types and tissues. The resulting isoforms vary in receptor affinity and biological activity and are natural ligands for the G protein-coupled receptors (GPCRs) CMKLR1, GPR1 and CCLR2. To date, the activation of CMKLR1 (chemokine-like receptor 1) by chemerin and its role in metabolism and metabolic disorders as well as inflammation is best understood.
Neuroblastoma (NB) is a malignancy of the sympathetic nervous system and the most common extracranial solid pediatric tumor. Several chemoattractant GPCRs have been suggested to promote tumor progression, angiogenesis and metastasis in NB. Although for some cancers a potential function has been suggested, the role of chemerin and its receptors in the NB tumor microenvironment remains unknown.
In our study, the screening of microarray databases and analysis of neuroblastoma expression data showed a correlation between high CMKLR1, GPR1 and CCLR2 expression and a reduction in the overall survival probability. Expression of CMKLR1, GPR1, and chemerin was shown in nine neuroblastoma cell lines using RT-PCR, Western blot and immunocytochemistry. Furthermore, chemerin and CMKLR1 were also detected in neuroblastoma tumor tissue by immunohistochemistry. Stimulation of NB cell lines with active chemerin induced calcium mobilization and increased phosphorylation of MEK1/2 and ERK1/2 indicating an activation of the MAPK signaling pathway. Furthermore, chemerin stimulation led to increased NF-κB phosphorylation and translocation to the nucleus. The induction of NF-κB mediated signaling was observed by luciferase reporter assay. TNFα, IL-1β or serum stimulation increased chemerin protein expression and secretion in neuroblastoma cells.
To assess the functional significance of chemerin and its receptors in neuroblastoma tumorigenesis, cell clones overexpressing or silenced for CMKLR1/ Chemerin/ GPR1 are used in NB animal models.
Citation Format: Conny Tuemmler, Igor Snapkov, Ugo L. Moens, Per Kogner, John Inge Johnsen, Baldur Sveinbjørnsson. Expression of chemerin and chemerin receptors in neuroblastoma: implications in tumorigenesis. [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 3279. doi:10.1158/1538-7445.AM2015-3279
Abstract 3307: Chemopotentiation by low dose fractionated radiation therapy in colon cancer cells
Authors: Smith Teresa , Parekh Palak R. , Chang Elizabeth T. , Chuong Michael , Carrier France 
Published: August 2015

Abstract
Response rates for patients with primary and metastatic colorectal cancer treated with modern chemotherapy regimens such as 5-FU, leucovorin, oxaliplatin (FOLFOX) have routinely exceeded 50% and are frequently as high as 60-70%. However, as in most chemotherapy regimens, toxicity to normal cells is often a significant limitation. Tumors of the gastrointestinal (GI) track are also sensitive to radiation but the inability to combine radiation therapy (RT) with full-dose chemotherapy can be detrimental to patients, particularly those that may have disseminated micrometastatic disease. Therefore, new treatment strategies that incorporate chemotherapy that could increase tumor response without increasing toxicity are highly desirable. Laboratory and clinical data suggest that using low-dose fractionated radiation therapy (LDFRT) as a chemopotentiator may allow for full-dose chemotherapy with improved efficacy without adding to the toxicity of the systemic treatment. Here we show that twice daily radiation doses as low as 0.15 Gy for three consecutive days can significantly increase FOLFOX killing efficiency in human colon cancer RKO cells. In addition, our data indicate that the chemopotentiation by LDFRT may be mediated by the stress inducible hnRNP A18 protein. Down regulation of hnRNP A18 sensitizes RKO cells to LDFRT and FOLFOX independently and increases further the chemopotentiation by LDFRT. Moreover, overexpression of hnRNP A18 increases radio-resistance and chemo-resistance to FOLFOX. hnRNP A18 is a new regulator of protein translation in cancer cells that specifically targets transcripts devoted to confer growth advantages. This data suggest that hnRNP A18 could be targeted to increase further the systemic effect of chemopotentation by LDFRT. The identification of hnNRP A18 as a new cellular pathway responsive to low dose radiation and its contribution to chemopotentiation provide a novel opportunity for better measurement of the therapeutic response and could contribute to the rationale designs of new mechanism based clinical trials.
Citation Format: Teresa Smith, Palak R. Parekh, Elizabeth T. Chang, Michael Chuong, France Carrier. Chemopotentiation by low dose fractionated radiation therapy in colon 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 3307. doi:10.1158/1538-7445.AM2015-3307