bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2015: Thrombospondin-1 is a targetable marker of invasive, mesenchymal- like melanoma cells
Authors: Behren Andreas , Jayachandran Aparna , Anaka Matthew , Hudson Christopher , Cebon Jonathan 
Published: May 2015

Abstract
Resistance to anti-cancer therapies arising from genetic heterogeneity is well understood. Less well characterised is the resistance to therapy proposed to occur via the plastic changes in melanoma cells generated by the impact of the tumor microenvironment. In melanoma, phenotypic-switching as means of plasticity has been well described and resembles, at least partially, an epithelial-to-mesenchymal transition (EMT). The presence of mesenchymal-like, invasive and slow-proliferating cells in melanoma, a highly aggressive cancer with intrinsic resistance to chemotherapy, is controversial and their potential contribution to therapeutic resistance has yet to be determined.
Methods: We examined melanoma cell lines for the presence of mesenchymal-like cells using CM-Dil, a membrane dye evenly distributed to daughter cells with each cell division as a marker of reduced cell division. Functional assays included invasion and motility assays, in vivo mouse xenograft models as well as an in vivo chicken neural crest transplantation assay. Genome-wide gene-expression profiling was performed using Illumina HT12 arrays.
Results: Here we show that mesenchymal-like cells are present in cell lines and in xenograft tumors, survive exposure to cytotoxic drugs and are invasive. Importantly, resistance was associated with a gene expression signature characterized by the expression of thrombospondin, TGFBI, genes associated with the extracellular matrix, and acquisition of increased invasiveness. This gene-expression pattern is reminiscent of an epithelial-to-mesenchymal transition in other solid cancers and a similar phenotype was detected after acquired resistance to the BRAF inhibitors PLX4720 and dabrafenib. Moreover, targeting thrombospondin in an in vivo model of melanoma cell plasticity and invasion led to the complete abrogation of the plastic and invasive potential of melanoma cells.
Conclusion: The results link therapeutic resistance to the presence of mesenchymal-like and invasive cells, and identify potential targets for novel therapies directed at eradicating this key melanoma subpopulation.
Citation Format: Andreas Behren, Aparna Jayachandran, Matthew Anaka, Christopher Hudson, Jonathan Cebon. Thrombospondin-1 is a targetable marker of invasive, mesenchymal- like melanoma cells. [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 2015. doi:10.1158/1538-7445.AM2014-2015
Abstract 2025: Multicellular tumor spheroid 3D models to decipher cancer cell biology and to evaluate anticancer drugs
Authors: Ducommun Bernard , Lobjois Valérie 
Published: May 2015

Abstract
MultiCellular Tumor Spheroid (MCTS) mimic the organization of a tumor and is considered as an invaluable model to study cancer cell biology and for the preclinical development of new antiproliferative drugs.
We will report how engineering of MCTS in association with new technological developments can be used to explore the regionalization and the effects of novel drugs. We will demonstrate the potential of these 3D models to study the kinetics aspects of the response on live spheroids expressing fluorescent reporters and markers using light sheet microscopy (SPIM).
We will also report the development of innovative microdevices dedicated to the study of the dynamics of MCTS formation and to the monitoring of mechanosensing and tumor growth-induced mechanical stress. We will present our latest advances on the characterization of these processes and on the use of these assays for the identification of new original targets and compounds.
Citation Format: Bernard Ducommun, Valérie Lobjois. Multicellular tumor spheroid 3D models to decipher cancer cell biology and to evaluate anticancer drugs. [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 2025. doi:10.1158/1538-7445.AM2014-2025
Abstract 2031: HMGB1 regulates pancreatic cancer initiation and pogression
Authors: Kang Rui , Zhang Qiuhong , Hou Wen , Chen Ruochan , Lotze Michael , Zeh Herbert , Tang Daolin 
Published: May 2015

Abstract
Most pancreatic ductal adenocarcinoma (PDAC), an almost uniformly lethal disease, is thought to arise from well-defined, non-invasive precursor lesions, termed pancreatic ductal intraepithelial neoplastic lesions (PanINs). Studies of human pancreatic carcinogenesis have been greatly facilitated by the development of a genetically engineered mouse model that expresses oncogenic K-Ras under a pancreatic promoter Pdx1-Cre:KrasG12D/+. A more detailed understanding of how this pathway accelerates pancreatic carcinogenesis may allow improved early detection, prevention, and therapeutic strategies. Our recent studies demonstrate that high mobility group box 1 (HMGB1) is a critical regulator of autophagy, a major pathway for degradation of effete proteins and damaged organelles. We found that conditional genetic ablation of HMGB1 limited to the pancreas (Pdx1-Cre;K-Ras G12D/+;HMGB1-/-; termed KCH mice) inhibits autophagy, promotes proliferation, activates normally quiescent pathways, and renders mice extraordinarily sensitive to K-RasG12D/+-driven pancreatic carcinogenesis. We found that the progression of PanINs from low grade PanIN1 to high grade PanIN3 was observed as early as three-seven days (normally three-nine months) after birth in KCH mice, suggesting a critical role of HMGB1 in regulation of the earliest events during pancreatic carcinogenesis. This extraordinarily rapid murine pancreatic cancer model that we have created will allow us to dissect the mechanism by which loss of HMGB1 contributes to the process.
Citation Format: Rui Kang, Qiuhong Zhang, Wen Hou, Ruochan Chen, Michael Lotze, Herbert Zeh, Daolin Tang. HMGB1 regulates pancreatic cancer initiation and pogression. [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 2031. doi:10.1158/1538-7445.AM2014-2031
Abstract 2032: TGF-β differentiates immortalized pancreatic epithelial cells to form duct architecture in 3D culture
Authors: Yamaguchi Takashi , Ikehara Sanae , Ikehara Yuzuru 
Published: May 2015

Abstract
A genetically engineered mouse (GEM) strain T26 having a transgene “CAG-loxP-βgeo-pA-loxP-SV40 tsA58 large T antigen (=tsTAg)-pA” was created by us, which expressed tsTAg in cells Cre/loxP recombination occurred. In a previous study, T26; Tie2-Cre mice were created, and their vascular and lymphatic endothelial cells expressing tsTAg could be cultured in vitro at 33°C (Yamaguchi et al., FEBS J., 2008). In this study, we established immortalized and cloned pancreatic epithelial cell lines from T26; Pdx1-Cre mice which expressed tsTAg in pancreatic epithelial cells in vivo by pancreas-specific Cre/loxP recombination. The cell lines were categorized into 1) ductal epithelial cell group which expressed CK19 and Sox9, and 2) acinar cell group which expressed Amylase2A of a digestive enzyme. In order to elucidate regulatory mechanisms of ductal cell differentiation and their plasticity, the immortalized ductal cell lines were cultured in collagen gel. A part of the cells formed spheroid or elongated and blanched architecture in the gel. Confocal or electron microscopic analysis indicated that their architectures had lumens with micro villi inside, and a part of them had tight junction at intercellular domain. It is noteworthy that the spheroid property changed into the elongated ductal (tubular) property by TGF-β stimulation in the 3D culture system, and the ductal architecture formation was suppressed by inhibitor of TGF-β signaling. 3D time-laps microscopic analysis demonstrated that a part of sphere-forming cells could change into duct-forming cells by TGF-β, which suggested existence of stem cells with susceptibility to TGF-β stimulation. The effect of TGF-β to change sphere-forming property into duct-forming property could be confirmed partially in some originally established murine pancreatic cancer cell lines. Taken together, these results suggested that TGF-β is an important factor for pancreatic duct and cancer differentiation and their architecture formation.
Citation Format: Takashi Yamaguchi, Sanae Ikehara, Yuzuru Ikehara. TGF-β differentiates immortalized pancreatic epithelial cells to form duct architecture in 3D culture. [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 2032. doi:10.1158/1538-7445.AM2014-2032
Abstract 2036: OncoPanel 3D: High-content characterization of 240 three-dimensional tumor spheroids for drug response profiling and biomarker discovery
Authors: Snead Katie , Hnilo Jim , Bernards Karen , Crane Jonathan M. , Nelson Brian , Angione Alison R. , McKinley Keith , Waikins Kate , Shah O. Jameel 
Published: May 2015

Abstract
While drug response profiling of cancer cells in two-dimensional culture has been a mainstay of predictive biomarker discovery and anti-cancer drug development, there are aspects of tumor biology that are not replicated in a two-dimensional cell culture environment. This is particularly true for solid tumor models where the three-dimensional organization of the tumor creates distinct, regional microenvironments that influence drug response. For example, as the radius of solid tumors approaches the diffusion limit of oxygen and other nutrients, the tumor core becomes hypoxic and accumulates metabolic waste products, resulting in cell death through mechanisms involving apoptosis and necrosis. Moreover, without proper vascularization, the tumor interior also exhibits increased interstitial pressure, which limits drug penetration into the tumor. We have characterized the three-dimensional growth of 240 cancer cell lines from various tumor origins by high-content imaging. This characterization involves the growth of tumor spheroids over 14 days and an assessment of tumor hypoxia in each model. The genomic traits associated with spheroid formation are also defined through genomic analysis. Finally, we provide validation and drug response data for several standard-of-care cancer therapeutics in pre-formed, three-dimensional tumor spheroid models. Drug profiling of this three-dimensional cell line panel offers new insights into drug response and can be used to prioritize drugs with improved tumor penetration or those with otherwise improved activity in three-dimensional models.
Citation Format: Katie Snead, Jim Hnilo, Karen Bernards, Jonathan M. Crane, Brian Nelson, Alison R. Angione, Keith McKinley, Kate Waikins, O. Jameel Shah. OncoPanel 3D: High-content characterization of 240 three-dimensional tumor spheroids for drug response profiling and biomarker discovery. [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 2036. doi:10.1158/1538-7445.AM2014-2036
Abstract 2039: Dynamic changes and regulation of circulating tumor cells that govern the metastasis of colorectal cancer
Authors: Tseng Ju-Yu , Yang Chih-Yung , Jiang Jeng-Kai , Lin Chi-Hung 
Published: May 2015

Abstract
Despite the growing public awareness and recent progress in multimodality therapy to the colorectal cancer (CRC), CRC still ranks high on the list of the most common and deadly cancers in the worldwide. The cause of CRC mortality is due mainly to the occurrence of distant metastasis, upon which the circulating tumor cells (CTCs), is thought to play an active role. CTCs could serve as a prognostic marker for mortality in clinical stage IV patients; however, the prognostic value of CTCs in early-stage patients remains uncertain. Here, we used EpCAM-postive/CD45-negative immunoselection and flow-cytometry to identify and quantify CTCs in CRC patients.
The number of mesenteric CTCs obtained from stage II patients was higher than those obtained for patients with stages I, III, or IV CRC. To explore the mechanisms underlying this clinical observation, we established an orthotopic (intra-cecal) tumor growth and metastasis mouse model. Cancer progression was monitored in real time with tumor cells expressing luciferase and GFP tag by using a bioluminescence imaging system and flow cytometery. We noticed that CTC dynamics was associated with a corresponding change in serum interleukin (IL)-17A and an opposing change in serum GM-CSF. Ablation of IL-17A by neutralizing antibodies and administration of GM-CSF effectively diminished the rise of CTCs and prevented metastasis in the mouse model. GM-CSF was through to help eliminating CTCs by boost host immunity, whereas IL-17A affected cancer cells intravasation by promoting cancer cell motility, matrix digestion and angiogenesis. We also noticed that IL-17 depletion could increase CD8+ to CD4+CD25+ ratio that might help CTCs clearance.
In CRC patients, serum levels of IL-17A positively correlated with the number of mesenteric CTCs and the patients' disease-free survival. Our results show that CTCs and IL-17A can serve not only as prognostic markers, but also therapeutic targets for CRC metastasis.
Citation Format: Ju-Yu Tseng, Chih-Yung Yang, Jeng-Kai Jiang, Chi-Hung Lin. Dynamic changes and regulation of circulating tumor cells that govern the metastasis of colorectal cancer. [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 2039. doi:10.1158/1538-7445.AM2014-2039
Abstract 2040: Adenomatous polyposis coli mediated signaling, self renewal and differentiation of breast epithelial cells
Authors: Lesko Alyssa , Nakshatri Harikrishna , Anjanappa Manjushree , Bhat-Nakshatri Poornima , Prosperi Jenifer 
Published: May 2015

Abstract
Breast cancer is the leading cause of cancer-related death in non-smoking women in the United States. Despite tremendous amounts of information about the etiology of breast cancer, many questions remain unanswered. It has been demonstrated that specific subtypes of breast cancer differ in their sensitivity to chemotherapeutic and targeted therapies. The oncogenic events and signaling pathways driving these tumor subtypes are distinct. This indicates that increased knowledge of the molecular events defining the unique subtypes will provide opportunities for novel therapeutic approaches tailored to fit the specific subtypes and will therefore lead to improvement in patient outcomes. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 18-70% of sporadic breast cancers depending on subtype. Oncomine database analysis revealed reduced expression of APC in aggressive estrogen receptor (ER) negative breast cancers compared to ER-positive breast cancer or normal breast. Using the ApcMin/+ mouse model, we identified pre-neoplastic lesions in the breast and enhanced breast tumorigenesis in the presence of the Polyoma middle T antigen (PyMT) oncogene. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. In this model of mouse mammary tumorigenesis, these changes occurred independent of Wnt/b-catenin signaling and required activation of focal adhesion kinase (FAK)/Src signaling, with a subsequent increase in cyclooxygenase-2 (COX-2). The applicability of these signaling pathways to human breast cancer remains unclear. Using the epithelial cell reprogramming assay for growing normal breast epithelial cells, we have begun to characterize expression of cell surface markers to delineate subtypes of epithelial cells. We have also assessed APC expression and correlated APC expression with risk and well-established clinical markers, such as ErbB2. Future studies will modulate APC expression in specific compartments of breast epithelial hierarchy to accomplish our objectives of dissecting the molecular alterations specifically downstream of APC loss and its role in the self-renewal and differentiation of breast epithelial cells.
Citation Format: Alyssa Lesko, Harikrishna Nakshatri, Manjushree Anjanappa, Poornima Bhat-Nakshatri, Jenifer Prosperi. Adenomatous polyposis coli mediated signaling, self renewal and differentiation of breast epithelial cells. [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 2040. doi:10.1158/1538-7445.AM2014-2040
Abstract 2043: Modeling the differential responses of cancer stem cells (CSCs) as heterogeneous versus homogenous populations in human cancers
Authors: Mancini Maria L. 
Published: May 2015

Abstract
Emerging data suggests that many human cancers including breast, brain, lung, colon, pancreatic and head and neck cancer are maintained by a subpopulation of self-renewing cells characterized as cancer stem cells that contribute to tumor growth and metastasis. Cancer stem cells have become an important target for new treatment paradigms as they may hold the key to solving treatment resistance and tumor recurrence. Paramount to the development of new therapies that preferentially target cancer stem cells is having predictable and clinically relevant models that accurately represent stem cell behavior and the tumor microenvironment. Examination of cancer stem cells both as a homogenous population and as a heterogeneous population interacting with other tumor cells is required for the development of effective treatments for stem cell driven tumor types. To address this we developed in vitro and in vivo cancer stem cell models of breast and pancreatic cancers to provide a comprehensive approach for preclinical research in these areas. Using the MDA-MB-231 and BxPC3 human cancer cell lines we are able to show the differential responses of cancer stem cells isolated from the parent lines to the standard chemotherapeutic agents docetaxel and gemcitabine with and without the small molecule inhibitor Reparixin specifically designed to inhibit cancer stem cells. Treatment response differences between homogeneous cancer stem cell versus heterogeneous populations were revealed in their growth, differentiation and invasiveness as determined by 2D and 3D tumorsphere assays. This response is also recapitulated in vivo using IVIS imaging to compare orthotopic tumor growth of isolated cancer stem cells and the parent lines treated with standard chemotherapeutics agents with or without combination Reparixin treatment. These results emphasize the need to employ a multifaceted approach to specifically target cancer stem cells in preclinical drug development to identify successful therapies for use as part of an overall treatment regimen in recurring or treatment resistant cancers.
Citation Format: Maria L. Mancini. Modeling the differential responses of cancer stem cells (CSCs) as heterogeneous versus homogenous populations in human cancers. [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 2043. doi:10.1158/1538-7445.AM2014-2043
Abstract 2063: Trojan horsing the blood-brain barrier with nanocarriers aided by adenosine receptor agonists
Authors: Awwad Nasir Al 
Published: May 2015

Abstract
Drug delivery to the central nervous system (CNS) is not easy compared to other body systems due to the presence of the blood brain barrier (BBB). It is essential that any delivery system to the CNS needs to be efficient and non-toxic. These features are fulfilled through tailored nanomicelles, non cross-linked and disulfide cross-linked micelles (NCM and DCM, respectively) and Polyvinyl alcohol-based polymeric nanoparticles. It has recently been reported that adenosine receptor agonists can modulate the permeability of the BBB. For example 5′-(N-Ethylcarboxamido)Adenosine (NECA) helps increase penetrability of the BBB membrane to macromolecules. We were able to demonstrate that similar strategy can be applied in mouse model for facilitating the penetration of NCM, DCM, and PVA-nanoparticles through the BBB. In the murine model we found that NECA stimulated the uptake of these nanoparticles to organs expressing adenosine receptors, especially the brain. DCM and NCM uptake was not seen in the brain without prior administration of NECA. NECA has been previously shown to alter tight junction adhesion molecules (Occludin) expressed on brain endothelial cells. NECA at 5.3 mg/kg best facilitated the penetration of both DCM and NCM at an optimal loading dosage of 33 mg/kg. NECA opened the BBB and facilitated the penetration of nanoparticles through the BBB at a constant rate. This allows potential for future drug-loading studies on a diverse scale for chemotherapeutics, kinase inhibitors, and other drug classes.
Note: This abstract was not presented at the meeting.
Citation Format: Nasir Al Awwad. Trojan horsing the blood-brain barrier with nanocarriers aided by adenosine receptor agonists. [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 2063. doi:10.1158/1538-7445.AM2014-2063