bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3898: Emerging role of Fra-1 as a novel target for radiosensitization in HPV-associated cancers
Authors: Tyagi Abhishek , Gupta Shilpi , Kuamr Prabhat , Bharti Alok C. , Das Bhudev C. 
Published: July 2017

Abstract
Background: Activator protein-1 (AP-1) plays a central role in HPV-mediated cervical and tongue cancer (subset of HNSCC). AP-1, a homo/heterodimeric protein composed of Jun and Fos family proteins, has been implicated in chemoradioresistance but the mechanism(s) remained unexplored. In the present study, AP-1 family protein Fra-1 has been shown to play a critical role in promoting radiosensitization in enriched cervical cancer stem-like cells (CaCxSLCs) and can serve as a target for drug intervention in cervical and other HPV associated cancers.
Experimental Procedure: Cervical cancer stem-like cells (CaCxSLCs) were isolated and enriched by sequential gating HPV+ve and HPV-ve human cervical cancer cell lines, SiHa, and C33a using a set of functional and phenotypic markers (ABCG2, CD49f, CD71, CD133) in defined conditioned media (DCM) with intermittent culturing. CaCxSLCs were also assessed for their cervicosphere forming ability, exclusion of DCV dye for generating SP cells, self renewability and quiescenceness.
Both CaCxSLCs and Non CaCxSLCs were exposed to different dose of UV irradiation and a herbal compound curcumin, a potent inhibitor of AP-1 was used to examine the role of AP-1 and its family proteins in the radiosensitization of cancer stem cells.
Results: Upon UV irradiation, CaCxSLCs showed a dose-dependent higher proliferation and highly increased AP-1 activity whereas it was completely abolished in non-stem cancer cells. CaCxSLCs also showed differential overexpression of c-Fos and c-Jun at transcript as well as in protein level. The loss of AP-1 activity and expression was accompanied by decrease in cell viability and proliferation in UV irradiated non-stem cancer cells. Interestingly, CaCxSLCs treated with curcumin prior to UV irradiation abolished AP-1 activity and a concomitant reduction in SP cells leading to abrogation of sphere forming ability, loss of proliferation, induction of apoptosis and the cells were poorly tumorigenic. The curcumin pre-treatment abolished the expression of c-Fos and c-Jun but upregulated Fra-1 expression in irradiated CaCxSLCs.
Conclusion: The study suggests a critical role of AP-1 protein in the manifestation of radioresistance but curcumin pretreatment helps in radiosensitizing CaCxSLCs through upregulation of Fra-1 which may serve as a potential target for elimination of radioresistant cancer stem cells in HPV-associated malignancies.
Note: This abstract was not presented at the meeting.
Citation Format: Abhishek Tyagi, Shilpi Gupta, Prabhat Kuamr, Alok C. Bharti, Bhudev C. Das. Emerging role of Fra-1 as a novel target for radiosensitization in HPV-associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3898. doi:10.1158/1538-7445.AM2017-3898
Abstract 3905: Development of anticancer aptamers targeting cancer stem cells
Authors: Chen Yuh-Ling , Hsieh I-Shan , Hsu Keng-Fu , Hong Tse-Ming 
Published: July 2017

Abstract
Background: Cancer stem cells (CSC), also called tumor initiating cells (TIC), are a small population of cancer cells within a tumor that drive the tumor initiation, metastasis, and resistance to chemotherapeutic drugs. An effective cancer stem cell targeting strategy by oligonucleotide-based approaches such as aptamers in diagnosis and treatment are urgently needed. In this study, we aimed to develop an effective aptamer-based biomarker for CSCs in cancer detection and therapy.
Material and methods: E-cadherin-null lung cancer cells, shEcad-A549, was confirmed with stemness properties and used as targeting cells. The isolation of DNA aptamers binding to CSCs was by using a Cell-SELEX (systematic evolution of ligands by exponential enrichment). By combining the aptamer-pull-down approach with proteomics, we identified the potential binding proteins of CSC-aptamer. Flow cytometry, gene silencing and lung cancer xenograft models were used to explore the functions of CSC-aptamer and its targeted protein in lung cancer formation.
Results: The aptamer AP-9R was identified to bind lung CSCs with high affinity and specificity. AP-9R reduced lung cancer cell stemness and migration but no apparent cytotoxicity. By using proteomic approaches, the target protein of AP-9R in non-small cell lung cancer was further identified and characterized its important role in cancer stemness. For CSCs detection, we developed AP-9R conjugated beads and confirmed their effective captured rate of lung CSCs in vitro. Moreover, administration of AP-9R significantly reduced lung tumor growth in the xenograft model.
Conclusions: Our data are moving closer to understand the significance of cancer stem cells during cancer progression and demonstrate that aptamer-based therapies will be useful as therapeutic and diagnostic agents for lung cancer.
Citation Format: Yuh-Ling Chen, I-Shan Hsieh, Keng-Fu Hsu, Tse-Ming Hong. Development of anticancer aptamers targeting cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3905. doi:10.1158/1538-7445.AM2017-3905
Abstract 3906: Targeting a novel G-protein coupled receptor (GPCR) for elimination of leukemia stem cells (LSC)
Authors: Voli Florida , Yi Hangyu , Gonzales-Aloy Estrella , Wang Jenny Yingzi 
Published: July 2017

Abstract
Acute myeloid leukemia (AML) is a lethal blood cancer. Clinical evidence has highlighted the critical role for leukemic stem cells (LSCs) in the high relapse rate of AML patients. Understanding the signaling pathways critical for LSC function will facilitate the development of new therapies to target LSCs. G protein-coupled receptors (GPCRs) are the most successful drug targets with approximately 36% of currently marketed drugs targeting human GPCRs (Rask-Andersen et al., Nat Rev Drug Discov 2011). Aberrant expression of GPCRs has been observed in various cancers and the importance of GPCRs in cancer stem cells has begun to be appreciated.
In this study, our gene expression profiling analysis identified a novel GPCR (hereafter named NG), which was suppressed in LSCs compared to normal hematopoietic stem cells. Overexpression of NG in pre-LSCs severely impaired leukemia initiation and progression in mice, whereas knockdown of NG significantly accelerated the disease onset. Our data also showed that NG overexpression substantially downregulated several well-known Wnt/β-catenin targets (e.g., Tcf7l2, c-Fos and Ccnd1). These data support a tumor suppressive role for NG in inhibiting leukemogenesis via downregulation of Wnt/β-catenin signaling.
Consistent with these observations, treatment with an agonist that specifically activates the NG signaling pathway induced a marked decrease in cell viability and growth in murine LSCs and in human AML THP-1 cells, but had no effects on human AML MOLM-13 cells. This agrees with our finding that NG specifically targets the Wnt/β-catenin signaling, and the inhibitory effect of the agonist might largely depend on β-catenin expression levels in human AML cells, wherein THP-1 has been reported to express endogenous β-catenin but MOLM-13 exhibits no detectable β-catenin expression (Man CH. et al. Blood 2015).
In summary, our data support a tumour suppressor role for NG in leukemogenesis and the forced expression of NG may provide a means to eradicate LSCs. Thus, restoring NG by the agonist treatment represents a promising therapeutic strategy for AML treatment.
Citation Format: Florida Voli, Hangyu Yi, Estrella Gonzales-Aloy, Jenny Yingzi Wang. Targeting a novel G-protein coupled receptor (GPCR) for elimination of leukemia stem cells (LSC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3906. doi:10.1158/1538-7445.AM2017-3906
Abstract 3907: Targeting cancer stem cells with microRNA therapeutics and particle radiation in challenging cancer models
Authors: Vares Guillaume , Saintigny Yannick , Sai Sei , Sugawara Hirotaka , Nakajima Tetsuo 
Published: July 2017

Abstract
Remarkable progress has been made in the understanding and treatment of human cancer, resulting in greatly improved survival for many patients. However, such achievements remain incomplete or out of reach for some hard-to-treat cancers, such as pancreatic cancer or triple-negative breast cancer. Chondrosarcoma is resistant to conventional radiation therapy and to chemotherapy. Innovative approaches focusing on those challenging cancer models are therefore highly expected. There is now wide acknowledgment that tumors are generally heterogeneous and that cancer treatment failure, relapse or metastasis may be related a small population of stem-like cells that are capable of self-renewing and of causing the different lineage of cancer cells comprising a tumor. These cancer stem cells (CSCs) are more radio-resistant than their non-CSC counterparts and have a distinct molecular signature. CSCs and differentiated cancer cells seem to coexist in a dynamic equilibrium influenced by the micro-environment and by specific micro-RNA expression patterns. The development of new therapeutic strategies (such as micro-RNA modulating strategies) that selectively target CSCs is currently receiving increasing attention. Particle radiation therapy (such as carbon-ion therapy) is effective at treating various radioresistant tumors and has already achieved promising results. Approaches combining high-LET radiation therapy and targeted-therapy have been suggested for tumors with bad prognosis.We have described a new molecular pathway in basal-like breast cells, resulting in the generation of breast CSCs. Maintenance of the CSC phenotype required the downregulation of miR-29 expression and the upregulation of Klf4 expression. Restoring miR-29 with mimic administration might therefore improve breast cancer therapy efficiency by targeting CSCs. For those reasons, we have evaluated the ability of several microRNA-modulating treatments to reverse CSC phenotype in three experimental in vitro models (pancreatic cancer, chondrosarcoma, triple-negative breast cancer), in combination with exposure spread-out Bragg peak (SOBP) carbon-ion beam (at the HIMAC medical accelerator). In triple-negative breast cells, miR-29 mimic administration increased radiation-induced cell death and decreased the proportion of CSCs. We identified several other microRNA mimic treatments capable of improving carbon-ion therapy efficiency by targeting radioresistant CSCs in those experimental models.
Citation Format: Guillaume Vares, Yannick Saintigny, Sei Sai, Hirotaka Sugawara, Tetsuo Nakajima. Targeting cancer stem cells with microRNA therapeutics and particle radiation in challenging cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3907. doi:10.1158/1538-7445.AM2017-3907
Abstract 3913: CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer
Authors: Wang Dingzhi , Sun Haiyan , DuBois Raymond N. 
Published: July 2017

Abstract
Emerging evidence suggests that the primary tumor induces the formation of pre-metastatic niches in certain distant organs. However, the mechanisms underlying the contributions of the primary tumor to pre-metastatic niche formation are not fully understood. Here we demonstrate that colorectal carcinoma cells secrete VEGF-A that stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in pre-metastatic liver tissue recruits CXCR2-positive myeloid-derived suppressor cells to form a pre-metastatic niche that ultimately promotes liver metastases. Importantly, we found that pre-metastatic liver-infiltrating MDSCs induce tumor cell survival without involvement of innate or adaptive immune responses. Our work not only reveals a novel mechanism by which the interactions of malignant cells with their stromal counterparts in the primary tumor contribute to the formation of a pre-metastatic niche that favors tumor cell survival, but also provides a rational for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Overall, our study provides the first evidence we know of showing that primary malignant cell-secreted VEGF-A stimulates tumor-associated macrophages to produce CXCL1 that recruits CXCR2-positive MDSCs to form a pre-metastatic niche which promotes liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to pre-metastatic niche formation at distant sites, but also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease.
Citation Format: Dingzhi Wang, Haiyan Sun, Raymond N. DuBois. CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3913. doi:10.1158/1538-7445.AM2017-3913
Abstract 3925: Integrative platform for the reconstruction and modeling of mechanically arrested single cells in the brain vasculature under spatial constraint and shear stress
Authors: Barrios Wendy V. Alvarez , Lu Huijie , Cowdrick Kyle R. , Galarneau Michelle , Jiang Lan , Lake Melinda , Yang Lin , Chen Danny , Hoelzle David , Peng Zhangli , Zhang Siyuan 
Published: July 2017

Abstract
During metastasis of breast cancer, tumor cells dissociate from the primary tumor, disseminate through the vasculature, and colonize secondary organs such as the brain, lungs, liver and bones. The mechanical arrest of circulating tumor cells (CTCs) in capillary beds is an essential step in the metastatic cascade for the successful early colonization of secondary organs. During mechanical arrest, tumor cells are subjected to extreme physical stresses such as shear stress and spatial constraint exerted by blood flow, as well as from compression by the constricting capillary on the restricted cell. These mechanical stresses may critically impact metastatic success. However, the precise physical and mechanical response of the disseminated tumor cells at the time of arrest in the vasculature to the forces of spatial constraint and shear stress remain largely unknown. Here we present an integrative platform that combines the use of a microfluidic device and computational model as a tunable system to reliably reproduce the mechanical arrest of single cells and quantitatively determine their physical response to precisely controlled mechanical forces of shear stress and spatial constraint. Using confocal microscopy and computational modeling, we found that during mechanical arrest, single tumor cells undergo extreme morphological deformations. Furthermore, the cell morphology is dependent on the magnitude of shear stress applied; with magnitudes above 60Pa inducing elongation, blebbing, and rupture of the cell membrane. Our results demonstrate that our integrative platform is a viable model system for the qualitative and quantitative study of physical cell behavior precisely at the metastatic stage of mechanical arrest. Particularly, our results highlight the direct influence of physical forces on the restricted tumor cell, and suggest the importance of these external cues as dynamic determinants of cellular processes and ultimately of metastatic success. We anticipate our platform to be a starting point for future studies seeking to understand the reciprocal molecular and biophysical interplay imposed by mechanical forces at the greatly understudied stage of mechanical arrest in metastasis.
Citation Format: Wendy V. Alvarez Barrios, Huijie Lu, Kyle R. Cowdrick, Michelle Galarneau, Lan Jiang, Melinda Lake, Lin Yang, Danny Chen, David Hoelzle, Zhangli Peng, Siyuan Zhang. Integrative platform for the reconstruction and modeling of mechanically arrested single cells in the brain vasculature under spatial constraint and shear stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3925. doi:10.1158/1538-7445.AM2017-3925
Abstract 3928: Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients
Authors: Whalen Diva , Wang Li , Widatalla Sarrah , Ochieng Josiah , Richmond Ann , Sakwe Amos 
Published: July 2017

Abstract
Patients with metastatic or end-stage breast cancer (BC) inevitably develop hypercalcemia, while up to 30% of BC patients develop cancer-induced hypercalcemia (CIH) in the absence of metastases or bone diseases. The commonly diagnosed mild increase in circulating calcium activates the calcium sensing receptor (CaSR) and has been shown to be associated with larger and more aggressive breast tumors in postmenopausal and premenopausal patients respectively. Whether differences in circulating calcium and/or specific inactivating CaSR variants play any role in disparities in BC outcomes remains unclear. DESIGN METHODS: We identified 199 BC cases and 384 age and genetic ancestry-matched controls with calcium assay and genotyping data from the Vanderbilt University DNA biorepository (BioVU) linked to de-identified electronic medical records. The linear mixed effects and codominant models were used to assess the relationship between inactivating CaSR mutations at rs1801725 (codon 986) and rs1801726 (codon 1011) and either circulating calcium levels or risk of high calcium-driven aggressive BC outcomes. RESULTS: We observed that circulating calcium levels were significantly higher in BC cases compared to control subjects (p=0.001) and interestingly, in subjects of African ancestry compared to Caucasians (p=0.001). The A986S mutant CaSR is common among Caucasians while the Q1011E mutant receptor is common among African Americans. However, only inactivating mutations at rs1801725 locus were significantly associated with higher calcium levels (p=0.006) and a higher (69%) risk of high calcium-driven aggressive BC outcomes compared to the wild type receptor. We also demonstrate that invasive BC cells are tolerant to sustained high calcium and that their adaptation to high calcium occurs via up-regulation of calcium-activated early response and malignancy-associated genes. CONCLUSION: These data suggest that inactivating CaSR polymorphisms at rs1801725 predispose BC patients to hypercalcemia and that high circulating calcium-driven aggressive disease outcomes occur via calcium modulated malignancy-associated genes such as MAGEC2/CT10.
Citation Format: Diva Whalen, Li Wang, Sarrah Widatalla, Josiah Ochieng, Ann Richmond, Amos Sakwe. Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3928. doi:10.1158/1538-7445.AM2017-3928
Abstract 3946: Chromosome instability drives phenotypic switching to metastasis
Authors: Gao Chong-Feng , Su Yanli , Koeman Julie , Essenberg Curt , Dykema Karl , Hudson Eric , Khoo Sok Kean , Woude George Vande 
Published: July 2017

Abstract
Chromosome instability (CIN) is the most striking feature of human cancers. However, how CIN drives tumor progression to metastasis remains elusive. Here we studied the role of chromosome content changes in generating the phenotypic dynamics that is required for metastasis. We isolated epithelial (E) and mesenchymal (M) clones from human carcinoma cell lines and showed that the E clones were able to generate mesenchymal variants, which had the potential to further produce epithelial revertants autonomously. The successive acquisition of invasive mesenchymal and then epithelial phenotypes recapitulated the steps in tumor progression to metastasis. Importantly, the generation of mesenchymal variants from clonal epithelial populations was associated with subtle changes in chromosome content, which altered the chromosome transcriptome and influenced the expression of genes encoding intercellular junction (IJ) proteins, while the loss of chromosome 10p, which harbors the ZEB1 gene, was frequently detected in epithelial variants generated from M clones. Knocking down these IJ genes in E cells induced a mesenchymal phenotype, while knocking down the ZEB1 gene in M cells induced an epithelial phenotype, demonstrating a causal role of chromosome content changes in phenotypic determination. Thus, our studies suggest a novel paradigm of tumor metastasis: primary epithelial carcinoma cells that lose chromosomes harboring IJ genes acquire an invasive mesenchymal phenotype, and subsequent chromosome content changes such as loss of 10p in disseminated mesenchymal cells generate epithelial variants, which can be selected for to generate epithelial tumors during metastatic colonization.
Citation Format: Chong-Feng Gao, Yanli Su, Julie Koeman, Curt Essenberg, Karl Dykema, Eric Hudson, Sok Kean Khoo, George Vande Woude. Chromosome instability drives phenotypic switching to metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3946. doi:10.1158/1538-7445.AM2017-3946
Abstract 3959: CCL18-recruited naïve CD4+ T cells are converted to tumor-infiltrating regulatory T cells in breast cancer and suppress antitumor immunity
Authors: Su Shicheng , Liao Jianyou , Liu Jiang , Liu Qiang , Song Erwei 
Published: July 2017

Abstract
Tumor-infiltrating regulatory T cells (Tregs) play a central role in tumor immunosuppression. However, it remains unclear whether they are directly recruited from peripheral blood or converted from infiltrating naïve T cells. Here, full-length TCR α/β repertoire analysis of different T cell subsets from peripheral blood, primary tumors and draining lymph nodes in patents suggests that Tregs in human breast cancer are mainly converted from tumor-infiltrating naïve CD4+ T cells. Infiltration of naïve CD4+ T cells and Tregs are closely correlated, both indicating poor prognosis for breast cancer patients. Naïve CD4+ T cells in the tumors are recruited by tumor-associated macrophages (TAMs) via CCL18. In addition, naïve T cells and memory T cells exhibit distinctive chemotactic response due to different expression of regulator of G-protein signaling 1(RGS1). Specific silencing CCL18 receptor-PITPNM3 in naïve CD4+ T cells using CD4 aptamer-siRNA blocks their chemotaxis, and thus reduces infiltrating Tregs and inhibits tumor progression in humanized mice. By comparison, silencing RGS1 in memory CD8+ T cells using CD8 aptamer-siRNA enhance their recruitment to tumors and anti-tumor immune response in vivo. These findings provide mechanistic insights for Treg enrichment in breast cancer and suggest that modification of the CCL18-PITPNM3-RGS1 signaling pathway may be an attractive strategy for anticancer immunotherapy.
Note: This abstract was not presented at the meeting.
Citation Format: Shicheng Su, Jianyou Liao, Jiang Liu, Qiang Liu, Erwei Song. CCL18-recruited naïve CD4+ T cells are converted to tumor-infiltrating regulatory T cells in breast cancer and suppress antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3959. doi:10.1158/1538-7445.AM2017-3959