bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-37: A patient-derived in vitro model of colorectal cancer: a perfusion culture system that recapitulates patient tumor composition and structure in 3-dimensions
Authors: Pfund William P. , Neeb Paul A. 
Published: May 2015

Abstract
Cancer medicine would benefit greatly from a practical technology that accurately predicts the sensitivity of individual patient tumors to drugs. Previously developed in vitro chemosensitivity models have generally failed to do this because they do not incorporate key aspects of the tumor microenvironment (TME), which clearly plays a role in drug resistance. There has been significant interest in patient-derived xenograft (PDX) chemosensitivity testing as an alternative to in vitro models, but the applicability of this approach is limited by engraftment percentages and growth rates.
We have developed an in vitro technology that is designed to recapitulate the 3D tissue architecture of patient-derived colorectal tumors including accessory (endothelial and immune) cells, starting with freshly excised tumor specimens. The system incorporates: 1) low-sheer, tangential flow of nutrient medium above and below an open, synthetic 3D cell scaffold; and 2) exchange of metabolic gasses via permeable membranes which separate the culture chamber core from gassing chambers located above and below the nutrient flow compartments. This design allows establishment of gas and nutrient gradients across the cell scaffold that closely mimic conditions in vivo.
Aliquots of mechanically and enzymatically dissociated, freshly excised, primary human colorectal adenocarcinomas were introduced into the 3D culture system and maintained for up to 3 weeks. Routine maintenance of the cultures involved partial medium exchanges as needed based on glucose concentrations in the circulating medium. The proportions and arrangement of key cell types (e.g., normal muscularis, tumor epithelium, stromal fibroblasts, endothelial cells, and immune cells) in the cultured explants were compared to those of the original tumor by standard histological techniques. Results revealed good agreement between the histology of the original tumor and that of the in vitro model. These results suggest that this model technology could be applied to individual patient drug selection as well as studies of colorectal cancer biology that are not feasible or practical in vivo.
Citation Format: William P. Pfund, Paul A. Neeb. A patient-derived in vitro model of colorectal cancer: a perfusion culture system that recapitulates patient tumor composition and structure in 3-dimensions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-37. doi:10.1158/1538-7445.AM2014-LB-37
Abstract LB-39: Human cone precursor-derived retinoblastoma tumors
Authors: Xu Xiaoliang L. , Singh Hardeep P. , Wang Lu , Qi Donglai , Poulos Bradford K. , Abramson David H. , Jhanwar Suresh C. , Cobrinik David 
Published: May 2015

Abstract
Retinoblastomas initiate in response to biallelic RB1 inactivation and loss of functional Rb protein, yet the cell of origin and cellular circuitry that sensitizes to Rb loss have been unclear. Here, we probed the cellular origin of retinoblastoma by assessing cell type-specific responses to shRNA-mediated Rb depletion in dissociated fetal retina, in intact retina, and in isolated cone precursor populations. In dissociated retinal cultures, RB1 knockdown induced S phase entry and proliferation of cells expressing markers of cone precursors (CRX + L/M opsin, or CRX + cone arrestin, or CRX + RXRγ) but not markers or other retinal cell types. Similarly, RB1 knockdown induced cone precursor proliferation in the undissociated retina and in prospectively isolated cone precursor populations. Proliferation of FACS-isolated cone precursors correlated with the induction of E2F-responsive genes and depended upon factors having strong cone precursor expression and crucial roles in retinoblastoma cell proliferation, including MDM2, MYCN, TRβ2, and SKP2. The proliferative response to Rb depletion was enhanced by co-depletion of the Rb-related p130 but was abrogated by co-depletion of p107, concordant with frequent p130 but not p107 losses in retinoblastoma tumors. Rb- and Rb/p130-depleted cone precursors proliferated in suspension and formed tumors in orthotopic xenografts with histologic features and protein expression profiles typical of differentiated human retinoblastomas. These findings indicate that post-mitotic human cone precursors are uniquely sensitive to the proliferative and oncogenic effects of Rb depletion and imply that human cone precursor circuitry collaborates with inactivating RB1 mutations to initiate retinoblastoma tumorigenesis.
Citation Format: Xiaoliang L. Xu, Hardeep P. Singh, Lu Wang, Donglai Qi, Bradford K. Poulos, David H. Abramson, Suresh C. Jhanwar, David Cobrinik. Human cone precursor-derived retinoblastoma tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-39. doi:10.1158/1538-7445.AM2014-LB-39
Abstract LB-41: Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models
Authors: Kovaks Zsofia , Werner Beat , Martin-Fiori Ernst , Bernasconi Michele 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor, with a very poor prognosis. Chemotherapeutical treatment of GBM is limited by the blood-brain barrier (BBB). This physical and metabolic barrier separates the blood from the brain parenchyma and prevents the entry of toxins but also of potentially useful chemotherapeutics from the blood into the brain.
Microbubble-enhanced focused ultrasound (MB-FUS) has been proposed to disrupt locally and reversibly the BBB to facilitate diffusion of drugs from the micro vasculature into brain tissue. The present study investigates the feasibility and the safety of such an approach in two syngenic mouse models of GBM (GL261 and SMA-560).
Local doxorubicin (DOX) concentration in MB-FUS sonicated normal brain tissue as well as in brain tumor tissue was increased as compared to the unsonicated control tissue in the contralateral hemisphere. Moreover, ultrasound mediated BBB disruption, in combination with DOX therapy, resulted in a significant increase of survival and in a slower disease progression in the two syngenic GBM mouse models.
In conclusion, our results confirm that MB-ultrasound might ultimately be an effective technology to improve the therapy of GBM, and they provide for the first time evidence that combining MB-FUS with DOX treatment is effective in syngenic mouse models for GBM which can serve as preclinical models to study the impact of immune system on the therapeutic application of MB-FUS chemotherapy.
Citation Format: Zsofia Kovaks, Beat Werner, Ernst Martin-Fiori, Michele Bernasconi. Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-41. doi:10.1158/1538-7445.AM2014-LB-41
Abstract LB-48: DCLK1 targeted monoclonal antibodies demonstrate therapeutic potential against pancreatic ductal adenocarcinoma
Authors: Qu Dongfeng , Weygant Nathaniel , May Randal , Chandrakesan Parthasarathy , Owen Daniel , Sureban Sripathi , Houchen Courtney 
Published: May 2015

Abstract
Doublecortin-like kinase 1 (DCLK1) is overexpressed and marks a population of tumor-initiating cells in pancreatic ductal adenocarcinoma (PDAC). It regulates key oncogenes, pluripotency factors, angiogenic factors, and epithelial mesenchymal transition (EMT) related transcription factors. Therefore, DCLK1 may be a novel therapeutic target in PDAC. In this study we evaluated whether DCLK1-targeted monoclonal antibodies (mAbs) demonstrate therapeutic activity against pancreatic cancer. Human pancreatic cancer cells (AsPC-1) were treated with mAbs against the C-terminal domain of human DCLK1 to assess their effect on gene expression, cell proliferation, migration, invasion, and tumorigenicity. Gene expression levels were analyzed by quantitative real-time RT-PCR. The proliferative and invasive potential of cells with or without mAb treatment were compared using a MTT assay for proliferation, wound healing assay for migration, and Matrigel coated transwell assay for invasion. Tumor xenografts originated from AsPC-1 cells in nude mice were also treated with these mAbs. Here we demonstrate that treating AsPC-1 cells with mAb against DCLK1 resulted in a more than 50% decrease in DCLK1 mRNA expression. The expression levels of several key tumor suppressor microRNAs, let7a, miR144, and miR200, were upregulated in cells treated with these mAbs. The expression levels of pancreatic cancer related oncogenes KRAS, NOTCH, and REG4, angiogenic factors, VEGFR1 and VEGFR2, and EMT related genes, ZEB1, ZEB2, SNAIL, SLUG, and TWIST, were significantly downregulated (among 30-50% reduction) in the cells treated with mAb against DCLK1. Furthermore, AsPC-1 cells exhibited more than 20% decrease in migration and more than 40% decrease in invasion following anti-DCLK1 mAb treatment. Moreover, AsPC-1 xenograft tumor volumes were reduced approximately 20% following mAb treatment. These data implicate the C-terminal of DCLK1 as a potential signal transduction regulator of DCLK1 in cancer via tumor suppressor microRNA related mechanism similar to siRNA mediated knockdown of DCLK1. These results suggest that utilizing mAb targeting DCLK1 may represent a potential novel therapeutic strategy to reduce the tumor stem-like cell subpopulation in PDAC.
Citation Format: Dongfeng Qu, Nathaniel Weygant, Randal May, Parthasarathy Chandrakesan, Daniel Owen, Sripathi Sureban, Courtney Houchen. DCLK1 targeted monoclonal antibodies demonstrate therapeutic potential against pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-48. doi:10.1158/1538-7445.AM2014-LB-48
Abstract LB-53: Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133
Authors: Ng Kai Y. , Chai Stella , Tong Man , Kwan Pak Shing , Chan Yuen Piu , Lee Terence Kin Wah , Wong Nathalie , Guan Xin-Yuan , Ma Stephanie 
Published: May 2015

Abstract
Tumor relapse after therapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive initial treatment. We have previously identified a CSC population derived from HCC that is characterized by the expression of the transmembrane glycoprotein, CD133. Despite our growing knowledge of the importance of a functional CD133+ liver CSC subset in driving HCC, the regulatory mechanism of CD133 is not known. Epigenetic changes are believed to be essential in the control of cancer and stem cells. We report here the dynamic epigenetic regulation of the functional liver CSC marker CD133 by promoter methylation and miR-142-3p regulation. Unlike in other tumor types, we found DNA methylation to only play a minor role in the control of CD133 expression in HCC. More importantly, our results revealed that miR-142-3p plays an integral part in the direct targeting of CD133. The interaction between the 3’UTR of CD133 and miR-142-3p was identified by in silico prediction and substantiated by luciferase reporter analysis. Expression of CD133 was found to be inversely correlated with miR-142-3p in a panel of liver cell lines and HCC clinical samples. Functional studies with miR-142-3p stably transduced in HCC cells demonstrated a diminished ability to self-renew, initiate tumor growth, invade, migrate, induce capillary tube formation in endothelial cells and resist standard chemotherapy. Rescue experiments whereby CD133 and miR-142-3p is simultaneously overexpressed compensated the deregulated ability of the cells to confer these cancer and stem cell-like features. In summary, our findings suggestion promoter methylation to only play a minor role in the regulation of CD133 in HCC; and that miR-142-3p directly targets CD133 to regulate its ability to confer cancer and stem cell-like features in HCC.
Citation Format: Kai Yu Ng, Stella Chai, Man Tong, Pak Shing Kwan, Yuen Piu Chan, Terence Kin Wah Lee, Nathalie Wong, Xin-Yuan Guan, Stephanie Ma. Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-53. doi:10.1158/1538-7445.AM2014-LB-53
Abstract LB-58: Role of mitochondrial ROS in activation of glioma stem cells and promotion of cancer development
Authors: Wang Feng , Yuan Shuqiang , Chen Gang , Kim Sangbae , Yang Jing , Li Feng , Lee Ju-Seog , Li Xiao-Nan , Xu Rui-hua , Huang Peng 
Published: May 2015

Abstract
Glioblastoma stem cells (GSCs) play a major role in brain tumor development, and they can be induced to undergo apparent differentiation morphology by serum. It is generally assumed that induction of differentiation by serum in cancer stem cells would reduce their ability to form tumors. However, how serum triggers such change in GSC differentiation status and whether it really affects their ability to form tumor remain unclear. Here we show that serum exposure activates mitochondrial respiration and causes an increase in mitochondrial ROS and stress responses, leading to NFκB activation and down-regulation of stem cell markers including CD133, Olig2, SOX2 and Notch1. Chemical perturbation of mitochondrial electron transport chain causes ROS increase in serum-induced GSCs and further decreases stem cell markers, while antioxidants reduce ROS and prevent the loss of stem markers. Surprisingly, the serum-induced GSCs exhibit greater ability to form tumor in both orthotopic and subcutaneous xenograft models, which can be suppressed by antioxidants. Our study suggests that stimulation of mitochondrial respiration and ROS generation is critical in activation of GSCs and promoting tumor development in vivo. Although exposure of glioma stem cells to serum causes a decrease in stem cell markers and a loss of neurosphere morphology, the seemingly differentiated GSCs surprisingly exhibit greater ability to form tumors in vivo. A decrease in expression of certain stem cell markers such as CD133 and SOX2 may not necessarily indicate a decrease in tumorigenicity in vivo, and that redox signaling may play a major role in regulation of tumor formation from cancer stem cells.
Citation Format: Feng Wang, Shuqiang Yuan, Gang Chen, Sangbae Kim, Jing Yang, Feng Li, Ju-Seog Lee, Xiao-Nan Li, Rui-hua Xu, Peng Huang. Role of mitochondrial ROS in activation of glioma stem cells and promotion of cancer development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-58. doi:10.1158/1538-7445.AM2014-LB-58
Abstract LB-60: Targeting stem cells in triple negative breast cancer through combined MEK and AKT inhibition
Authors: Zhang Kevin , McDermott Sean P. , Wicha Max S. 
Published: May 2015

Abstract
Breast cancer stem cells (CSCs) are hypothesized to be involved in tumor metastasis, dormancy, and eventual recurrence. Among the molecular subtypes of breast cancer, triple negative (i.e. lacking HER2 amplification and estrogen and progesterone receptors) cancers have the highest frequency of CSCs with cytotoxic chemotherapy being the only established treatment option. Breast CSCs are relatively resistant to cytotoxic chemotherapy and radiation treatment indicating new treatment modalities are needed. Breast CSCs can be identified using flow cytometry with the cell surface marker profile CD44+CD24-EpCAM+ or by intracellular expression of aldehyde dehydrogenase (ALDH+). Previously, we identified a role for AKT signaling in the survival of breast CSCs. Here, we have tested if inhibition of MEK and AKT signaling with two small molecules, GSK1120212 and GSK690693, respectively, were able to reduce the frequency and overall number of CD44+CD24-EpCAM+ and/or ALDH+ CSCs in multiple triple-negative breast cancer cell lines. Our results suggest that either the CD44+CD24-EpCAM+ or ALDH+ fraction are sensitive to three days of combined inhibitor treatment. Within the MDA-MB-468 cell line, there is more phospho AKT (S473) and phospho MEK1/2 (S218/S222) signaling in both ALDH+ and CD44+CD24-EpCAM+ cells compared to non-stem cells. Furthermore, there is more phospho MEK1/2 in ALDH+ cells compared to CD44+CD24-EpCAM+ and more phospho AKT in CD44+CD24-EpCAM+ cells compared to ALDH+ CSCs. Together, these results highlight the possibility of using a combination of these agents in clinical trials to target triple-negative breast CSCs.
Citation Format: Kevin Zhang, Sean P. McDermott, Max S. Wicha. Targeting stem cells in triple negative breast cancer through combined MEK and AKT inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-60. doi:10.1158/1538-7445.AM2014-LB-60
Abstract LB-62: Inhibitor of differentiation 4 (ID4) maintains mammary stem cell homeostasis and identifies a poor-prognosis subset of basal-like breast cancers with a putative stem cell of origin
Authors: Junankar Simon , Baker Laura , Yun Kyuson , Swarbrick Alexander 
Published: May 2015

Abstract
Basal-like breast cancers (BLBC) are heterogenous, poorly differentiated and present with limited therapeutic opportunities and a poor prognosis. We have investigated the role of the HLH transcription factor ID4 in breast stem cells and basal breast cancer aetiology. Using an Id4GFP knock-in mouse and single cell gene expression studies we show that ID4 defines a subset of Cd24+Cd29hi basal mammary epithelial cells enriched for stem cell gene expression and mammary repopulating capacity. Homozygous deletion of Id4 followed by mammary transplantation reveals a cell-autonomous requirement for Id4 in mammary ductal morphogenesis in vivo. shRNA-mediated depletion of Id4 in the Comma-D mammary stem cell line in vitro shows that Id4 is required for epithelial cell proliferation. Conversely, over-expression of Id4 maintains the stem cell pool by restricting luminal differentiation of Comma-D cells. This effect of Id4 is mediated via suppression of BrCa1 expression and the Notch-Elf5 axis. In clinical breast cancer specimens, ID4 expression is absent in luminal tumours but very high in approximately half of all BLBCs, a proportion of which possess ID4 gene amplification. These tumours are characterized by unique transcriptomes with many features of mammary stem cells. Furthermore, ID4-positive BLBCs have a very poor prognosis across multiple independent tissue cohorts. This study identifies ID4 as a master regulator of mammary stem cell homeostasis and suggests that a subset of aggressive BLBCs derive from a primitive mammary stem or progenitor cell with basal characteristics.
Citation Format: Simon Junankar, Laura Baker, Kyuson Yun, Alexander Swarbrick. Inhibitor of differentiation 4 (ID4) maintains mammary stem cell homeostasis and identifies a poor-prognosis subset of basal-like breast cancers with a putative stem cell of origin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-62. doi:10.1158/1538-7445.AM2014-LB-62
Abstract LB-64: Immune modulatory effects of mesenchymal stem cells on regulatory T cells in mouse glioma model
Authors: Moon Kyung-Sub , Wainwright Derek A. , Balyasnikova Irina V. , Kim Chung Kwon , Ko Yoo Seung , Kim Kyung Keun , Lesniak Maciej S. 
Published: May 2015

Abstract
Objective: Although mesenchymal stem cells (MSCs) have been investigated as a vector in stem cell-based therapy for malignant glioma, there has been a debate about the exact role of MSCs in tumor microenvironment. From an immunnological aspect, MSCs have been reported to inhibit T cell proliferation and to increase CD4+FoxP3+ regulatory T cells (Tregs). They also have been investigated as a potent immune suppressor in several clinical situations including autoimmune diseases. However, whether MSCs have an immune modulatory effect on Tregs in malignant gliomas or not has not been established.
Materials & methods: The author explored the impact of MSCs on freshly sorted CD4+ T cells or already activated Tregs in vitro to determine whether MSCs have different influences on naive T cells and Tregs. Furthermore, using orthotropic mouse glioma model, the author investigated MSC's effect on Tregs during tumor progression.
Results: The authors observed that MSCs decreased Treg conversion from naive T cells and Treg proliferation, without affecting the proportion of natural / induced Treg [nTreg; CD4+FoxP3+Helios+ / iTreg; CD4+FoxP3+Helios-]. When co-cultured with already activated Tregs, however, MSCs did not affect Treg induction and proliferation, but decreased the proportion of iTreg. With an intracranially implanted GL261 cell-based orthotropic mouse model, co-injection of MSCs with tumor cell implantation slightly increased Treg recruit into the tumor and decreased the proportion of iTreg. When MSCs were injected after glioma formation, there was no significant effect of MSCs on Treg recruit and phenotypic changes. Furthermore, there was a lower level of cytokine expressions including TGF-β, INF-γ, IL-2, and IL-1β in Tregs cocultured with MSCs than that in solely cultured Tregs. Increased gene expression of IL-6, CCL17, and TGF-β, or decreased gene expression of CCL2 in MSCs may be relevant to the phenotypic changes of cocultured Tregs.
Conclusions: This study demonstrates that MSCs mainly inhibit iTreg, leading to a relative increase of the proportion of nTregs in mouse glioma model, possibly throughIL-6 signaling pathway. With a better understanding for critical factors and immunological consequences for the altered Treg phenotype in glioma, future experiments will be needed to elucidate the immunological impact of MSCs on Tregs in malignant glioma.
Citation Format: Kyung-Sub Moon, Derek A. Wainwright, Irina V. Balyasnikova, Chung Kwon Kim, Yoo Seung Ko, Kyung Keun Kim, Maciej S. Lesniak. Immune modulatory effects of mesenchymal stem cells on regulatory T cells in mouse glioma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-64. doi:10.1158/1538-7445.AM2014-LB-64