bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A53: The specific FMS kinase inhibitor, DCC-3014, durably inhibits FMS kinase in vivo and blocks cancer bone invasiveness
Authors: Smith Bryan D. , Kaufman Michael D. , Leary Cynthia B. , Hood Molly M. , Lu Wei-Ping , Turner Benjamin A. , Vogeti Subha , Wise Scott C. , Flynn Daniel L. 
Published: May 2015

Abstract
Within the tumor microenvironment, tumor-associated macrophages (TAMs) rely on signaling through FMS kinase to promote tumor growth, angiogenesis, vasculogenesis, and metastasis. In addition, FMS-expressing macrophages communicate with the adaptive immune system, which can lead to cancer immunotolerance. Osteoclasts also depend on FMS kinase for differentiation and growth, and play a direct role in the ability of a tumor to metastasize to the bone and progress. Taken together, FMS kinase is an excellent target for small molecule therapy of tumor growth and bone metastasis. Using Deciphera Pharmaceuticals' approach to kinase inhibition, potent and specific FMS kinase inhibitors have been identified that achieve single digit nanomolar inhibition in biochemical and cellular assays of FMS activity. Due to their binding mode, these inhibitors retain potency in the presence of high ATP concentrations and also exhibit long off-rates from FMS kinase. Development candidate DCC-3014 is highly selective, inhibiting no other kinases within 100-fold of FMS potency, including related kinases KIT, PDGFRs, FLT3, and VEGFR2. DCC-3014 exhibits potent and durable inhibition of FMS in vivo in a pharmacokinetic/pharmacodynamic model. In a variety of cancer models, DCC-3014 or related analogs slow tumor growth, decrease tumor-promoting macrophages, and protect against osteolytic bone invasion. DCC-3014 is currently undergoing formal preclinical development.
Citation Format: Bryan D. Smith, Michael D. Kaufman, Cynthia B. Leary, Molly M. Hood, Wei-Ping Lu, Benjamin A. Turner, Subha Vogeti, Scott C. Wise, Daniel L. Flynn. The specific FMS kinase inhibitor, DCC-3014, durably inhibits FMS kinase in vivo and blocks cancer bone invasiveness. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A53. doi:10.1158/1538-7445.CHTME14-A53
Abstract A69: MCT-1 expression promotes neoplastic multinucleation through the Src/p190B signaling activation in triple-negative breast cancer cells
Authors: Wu Meng-Hsun , Chen Yen-An , Chen Hsiao-Huei , Chang Ko-Wei , Chang I-Shou , Wang Lu-Hai , Hsu Hsin-Ling 
Published: May 2015

Abstract
Multinucleation is associated with malignant neoplasm; however, the molecular mechanism underlying the nuclear abnormality remains unclear. Loss or mutation of PTEN is frequently implicated in the development of malignancies. We now demonstrate that increased expression of the oncogene MCT-1 antagonizes PTEN gene expression, protein stability and activation, thereby further promoting PI3K/AKT signaling and survival rate of the PTEN-deficient cells. MCT-1 interacts with p190B and Src in the triple negative breast cancer cells, supporting they are in proximity of the signaling complexes in vivo. MCT-1 overexpression and PTEN loss synergistically augmented the Src/p190B signaling function leading to inhibition of RhoA activity. Under such condition, the incidence of mitotic catastrophes including spindle multipolarity and cytokinesis failure were enhanced, driving a Src/p190B-dependent neoplastic multinucleation. Reduced MCT-1 expression by shRNA dramatically repressed the Src/p190B function and improved the nuclear structure, as well as suppressed tumorigenicity of the PTEN-null triple negative breast cancer cells. Consistent with the oncogenic effects in vitro, clinical evidence has confirmed that MCT-1 and p190B genes are highly expressed in human breast cancers. Accordingly, MCT-1 gene induction is recognized as a potentially indicator of breast tumor development. Abrogating MCT-1 function may be a promising strategy for treatment of the triple negative breast cancer involving aberrant activation of Src and/or dysfunction of PTEN.
Citation Format: Meng-Hsun Wu, Yen-An Chen, Hsiao-Huei Chen, Ko-Wei Chang, I-Shou Chang, Lu-Hai Wang, Hsin-Ling Hsu. MCT-1 expression promotes neoplastic multinucleation through the Src/p190B signaling activation in triple-negative breast cancer cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A69. doi:10.1158/1538-7445.CHTME14-A69
Abstract A72: Next-generation sequencing of disseminated tumor cells
Authors: Møller Elen K. , Kumar Parveen , Voet Thierry , Peterson April , Loo Peter Van , Mathiesen Randi , Fjelldal Renate , Grundstad Jason , Borgen Elin , Baumbusch Lars O. , Naume Bjørn , Børresen-Dale Anne-Lise , Nord Silje , Kristensen Vessela N. 
Published: May 2015

Abstract
Disseminated tumor cells (DTCs) detected in the bone marrow have been shown as an independent prognostic factor for women with breast cancer. However, the mechanisms behind the tumor cell dissemination are still unclear and more detailed knowledge is needed to fully understand why some cells remain dormant and others metastasize. Sequencing of single cells has opened for the possibility to dissect the genetic content of subclones of a primary tumor, as well as DTCs. Previous studies of genetic changes in DTCs have employed single-cell array comparative genomic hybridization which provides information about larger aberrations. To date, next generation sequencing provides the possibility to discover new, smaller and copy neutral genetic changes. In this study, we performed whole genome amplification and subsequently next generation sequencing to analyze DTCs from two breast cancer patients. We compared copy number profiles of the DTCs and the corresponding primary tumor generated from sequencing and SNP-CGH data, respectively. While one tumor revealed mostly whole arm gains and losses, the other had more complex alterations, as well as subclonal amplification and deletions. Whole arm gains or losses in the primary tumor were in general also observed in the corresponding DTC. Both primary tumors showed amplification of chromosome 1q and deletion of parts of chromosome 16q, which was recaptured in the corresponding DTCs. Interestingly, clear differences were also observed, indicating that the DTC underwent further evolution at the copy number level. This study provides a proof-of-principle for sequencing of DTCs and correlation with primary copy number profiles. The analyses allow insight into tumor cell dissemination and show ongoing copy number evolution in DTCs compared to the primary tumors.
Note: This abstract was not presented at the conference.
Citation Format: Elen K. Møller, Parveen Kumar, Thierry Voet, April Peterson, Peter Van Loo, Randi Mathiesen, Renate Fjelldal, Jason Grundstad, Elin Borgen, Lars O. Baumbusch, Bjørn Naume, Anne-Lise Børresen-Dale, Silje Nord, Vessela N. Kristensen. Next-generation sequencing of disseminated tumor cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A72. doi:10.1158/1538-7445.CHTME14-A72
Abstract A74: TGF-β in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma
Authors: Natsuizaka Mitsuteru , Kagawa Shingo , Whelan Kelly , Ohashi Shinya , Ohnishi Shunsuke , Suda Goki , Sakamoto Naoya , Rustgi Anil K. , Nakagawa Hiroshi 
Published: May 2015

Abstract
There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44 (CD44H). CD44H cells have cancer stem-like characteristics and as few as ten CD44H cells can form tumors in an athymic nude mouse. Epithelial-mesenchymal transition (EMT) has a critical role to maintain CD44H cells in ESCC. Notch1-mediated signaling may facilitate either EMT or squamous-cell differentiation in a context-dependent manner. However, detailed mechanism how Notch signaling promotes either EMT or differentiation remains unclear. We investigated how TGF-β in tumor microenvironment might influence Notch signaling to maintain CD44H cells via EMT in ESCC. TGF-β promoted EMT and enriched CD44H cells by activating Notch1 and ZEB1 and suppressing Notch3, while in absence of TGF-β, Notch1 rather activated Notch3, one of pivotal transcription factors in keratinocyte differentiation, led to keratinocyte differentiation. Highly conserved binding sites of ZEB1 exist in the 2nd intron of Notch3. ZEB1 induced by TGF-β bound to the 2nd intron of Notch3 and sharply suppressed the Notch3 transcription, confirmed by CHIP and luciferase assay. Thus TGF-β and Notch1 cooperatively promote EMT and maintain tumor initiating cells. TGF-β signaling influences the tumor initiating capacity of ESCC by modulating novel opposing activities of Notch1 and Notch3 in EMT, and may have translational implications.
Citation Format: Mitsuteru Natsuizaka, Shingo Kagawa, Kelly Whelan, Shinya Ohashi, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto, Anil K. Rustgi, Hiroshi Nakagawa. TGF-β in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A74. doi:10.1158/1538-7445.CHTME14-A74
Abstract A77: Hematopoietic stem cell-derived adipocytes promote tumor progression
Authors: Xiong Ying , Laws Dayvia A. , LaRue Amanda C. 
Published: May 2015

Abstract
The risk of developing a variety of tumors is increased under the condition of obesity or excess adiposity. Adipose tissue, apart from its critical role as the energy storage depot, contributes to the composition of tumor microenvironment that influences tumor behavior. It has generally been believed that bone marrow cells giving rise to adipocytes are mesenchymal stem cells (MSCs). Our previous study based on a single hematopoietic stem cell (HSC) transplantation model has identified a novel source of adipocytes from HSCs via progenitors for monocytes/macrophages. When cultured under adipogenic conditions, bone marrow-derived monocyte progenitors differentiated into adipocytes that are positive for Oil Red O staining, and secrete various adipokines including adiponectin, HGF, IGF-1 and MCP-1. These HSC-derived adipocytes underwent further maturation when embedded in matrigel and injected subcutaneously into syngeneic C57Bl/6 mice. To better understand the role of HSC-derived adipocytes in tumor progression, we tested the proliferative and migratory capacities of murine melanoma cells (B16F1) and breast cancer cells (EO771) under the influence of HSC-derived adipocytes. Conditioned medium from HSC-derived adipocyte culture (Ad-CM) supported cell proliferation and enhanced cell migration for both tumor types. We found IGF-1 plays a more important role in EO771 cell proliferation and HGF is indispensible for B16F1 cell migration, which correlate with the observations that B16F1 and EO771 cells express significantly more cMet and IGF-1R, respectively. When co-injected with B16F1 or EO771 cells into C57Bl/6 mice, HSC-derived adipocytes accelerated both melanoma and breast tumor growth, with HSC-derived adipocytes being more effective for B16F1 tumor growth than EO771 tumor growth. Taken together, we conclude that HSC-derived adipocytes regulate melanoma and breast tumor progression with different mechanisms. The ongoing work is directed to further delineate the function, mechanism and regulation of HSC-derived adipocytes in different tumor microenvironments.
Citation Format: Ying Xiong, Dayvia A. Laws, Amanda C. LaRue. Hematopoietic stem cell-derived adipocytes promote tumor progression. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A77. doi:10.1158/1538-7445.CHTME14-A77
Abstract B18: Blocking α4β1 integrin interaction with matrix metalloproteinase-9 overcomes stroma-induced resistance of chronic lymphocytic leukemia cells to fludarabine and arsenic trioxide
Authors: Amigo-Jiménez Irene , Bailón Elvira , Ugarte-Berzal Estefanía , García-Marco José Antonio , Garcia-Pardo Angeles 
Published: May 2015

Abstract
Chronic lymphocytic leukemia (CLL) progression is determined by CLL cell accumulation in lymphoid organs, where they receive survival signals that impair therapeutic treatments. MMP-9 is a microenvironment component and we have shown that induces a signalling pathway that leads to CLL cell survival. We have now studied whether MMP-9 is involved in the response to cytotoxic agents such as fludarabine and arsenic trioxide (ATO). Both agents upregulated MMP-9 (mRNA and protein) and enhanced its binding to CLL cells. Cell-associated MMP-9 was restricted to early apoptotic cells and totally dependent on apoptosis onset, suggesting a role in the response to these drugs. Indeed, anti-MMP-9 antibodies accelerated apoptosis. Moreover, MEC-1 cells (CLL-derived) stably transfected with MMP-9 were more resistant to drug-induced apoptosis than Mock-transfected cells. Western blot analyses revealed that MMP-9 prevented down regulation of anti-apoptotic Bcl-2 family members. Therefore, MMP-9 likely represents a compensatory survival response that contributes to drug resistance. Additionally, culturing CLL cells with bone marrow stromal cells (BMSC) prevented the apoptotic effect of ATO and this was nearly completely reverted with anti-MMP-9 antibodies. Blocking α4β1 integrin (MMP-9 receptor) and/or αLβ2 integrin (ICAM-1 receptor) also overcame stroma-induced survival. This was also partially achieved by culturing CLL cells with BMSC-conditioned medium, indicating that both cell adhesion and soluble factors contributed to the observed drug resistance. To determine the mechanisms involved, the effect of blocking several signalling pathways was studied. Inhibiting the PI3K/Akt or focal adhesion pathways with specific inhibitors significantly restored the sensitivity of CLL cells to ATO. Therefore, our results highlight the role of MMP-9 in CLL drug resistance and indicate that concomitant targeting of MMP-9 may improve the CLL response to treatment. Supported by grants SAF2012-31613 and RD12/0036/0061 (AGP) from the Ministry of Economy and Innovation, Spain; S2010/BMD-2314 (AGP) from the Comunidad de Madrid/European Union, and by a grant from the Fundación Puerta de Hierro, Madrid (JAGM).
Citation Format: Irene Amigo-Jiménez, Elvira Bailón, Estefanía Ugarte-Berzal, José Antonio García-Marco, Angeles Garcia-Pardo. Blocking α4β1 integrin interaction with matrix metalloproteinase-9 overcomes stroma-induced resistance of chronic lymphocytic leukemia cells to fludarabine and arsenic trioxide. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B18. doi:10.1158/1538-7445.CHTME14-B18
Abstract B29: GILZ mediates glucocorticoid action and inhibits hypoxia-induced COX-2 expression in A549 cells
Authors: Lim WonChung , Lee YoungJoo 
Published: May 2015

Abstract
The COX-2/PGE2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumourigenesis. Glucocorticoid receptor (GR) strongly suppresses COX-2 expression induced by inflammatory stimuli. However, the role of GR pathway on COX-2 induction by hypoxia and the mechanisms involved are not known. We examined whether the hypoxia induction of COX-2 was under the influence of glucocorticoid; we found that COX-2 promoter activity and mRNA and protein levels were depressed by dexamethasone and antagonized by the glucocorticoid receptor (GR) antagonist RU486. Overexpression of glucocorticoid-induced leucine zipper (GILZ) inhibited hypoxia-induced COX-2 promoter activity, and knockdown of GILZ by shRNA reduced glucocorticoid inhibition of hypoxia-induced COX-2 expression. Finally, we show that dexamethasone and GILZ inhibits cell invasion by hypoxia in A549 cells. Our results suggest that GR inhibits the hypoxic induction of COX-2 expression via GILZ and regulates cell invasion under hypoxia in A549 cells.
Citation Format: WonChung Lim, YoungJoo Lee. GILZ mediates glucocorticoid action and inhibits hypoxia-induced COX-2 expression in A549 cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B29. doi:10.1158/1538-7445.CHTME14-B29
Abstract B37: Phenotypic analysis of single cells dissociated from solid tumors
Authors: Ruitenberg Joyce J. , Middlebrook Aaron , Suni Maria , Hahn Friedrich , Snowden Eileen , Porter Warren , Ferguson Mitchell , Blaesius Rainer , Ghanekar Smita A. 
Published: May 2015

Abstract
Current methods for solid tumor analysis may be inadequate for addressing both the heterogeneity of tumor cells and the components of the tumor microenvironment. Comprehensive analysis requires the ability to analyze tumor biopsy specimens at the single-cell level. A better understanding of how the tumors are behaving at a cellular level, in relation to the other cells within the tumor microenvironment, could lead to more accurate and specific treatment, and better patient prognosis. Evaluation of tumor derived single cells by flow cytometry could provide unique information that is not readily obtained from current methods.
Here we demonstrate the single-cell analysis of solid tumors from breast and colorectal cancers. Since single-cell analysis of solid tumors may not occur at the collection site, it is important that tumors be preserved in order to retain their characteristics during transport. Using tumors from PDX mouse models, and human samples, different preservatives were evaluated for their effects on cellular viability and surface marker expression. Following shipment of the tumor samples in preservation solutions, the solid tumors were dissociated into single-cell suspensions using enzyme cocktails containing collagenase. Phenotypic evaluation was performed using flow cytometry after staining the single cells with monoclonal antibody panels specific for either tumor or immune cells.
The results indicate that the dissociation method did not seem to adversely impact the expression of surface proteins. We demonstrate that it is feasible to analyze dissociated tumor cell populations with relevant surface markers. Analysis of the data revealed distinct phenotype patterns for single cells dissociated from breast and colorectal cancers. Further extensive evaluation of heterogeneity in these tumor types could reveal phenotypic signatures that may be clinically relevant.
Citation Format: Joyce J. Ruitenberg, Aaron Middlebrook, Maria Suni, Friedrich Hahn, Eileen Snowden, Warren Porter, Mitchell Ferguson, Rainer Blaesius, Smita A. Ghanekar. Phenotypic analysis of single cells dissociated from solid tumors. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B37. doi:10.1158/1538-7445.CHTME14-B37
Abstract B48: Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling
Authors: Achyut B.R , Bader David , Robles Ana , Darawarlee Wanga , Harris Curtis , Ried Thomas , Yang Li 
Published: May 2015

Abstract
Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelial homoeostasis. However, the underlying mechanisms remain to be elucidated. Here we report that deletion of the gene encoding TGF-ß receptor 2 (Tgfbr2) in the stromal fibroblasts (Tgfbr2fspKO) induces inflammation and significant DNA damage in the neighboring epithelia of the forestomach. This results in loss or down-regulation of cyclin-dependent kinase inhibitors p15, p16, and p21, which contribute to the development of invasive squamous cell carcinoma (SCC). Anti-inflammation treatment restored p21 expression, delayed tumorigenesis, and increased survival of Tgfbr2fspKO mice. Our data demonstrate for the first time that inflammation is a critical player in the epigenetic silencing of p21 in tumor progression. Examination of human esophageal SCC showed a down-regulation of TGFß receptor 2 (TßRII) in the stromal fibroblasts, as well as increased inflammation, DNA damage, and loss or decreased p15/p16 expression. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of TßRII in the stroma.
Citation Format: B.R Achyut, David Bader, Ana Robles, Wanga Darawarlee, Curtis Harris, Thomas Ried, Li Yang. Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B48. doi:10.1158/1538-7445.CHTME14-B48