bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4399: Hypoxia as a driver of myeloid-derived suppressor cell recruitment in hepatocellular carcinoma via CCL26/CX3CR1
Authors: Chiu David Kung-Chun , Xu Iris Ming-Jing , Lai Robin Kit-Ho , Tse Aki Pui-Wah , Wei Larry Lai , Koh Hui-Yu , Lo Regina Cheuk-Lam , Wong Chun-Ming , Ng Irene Oi-Lin , Wong. Carmen Chak-Lui 
Published: July 2016

Abstract
Background and Objective: Myeloid-derived suppressor cells (MDSCs) accumulate in tumors and highly pro-tumorigenic. These MDSCs exhibit inhibitory functions against effector T cells and natural killer cells in tumor sites, as well as secrete pro-angiogenic factors or differentiate to endothelial cells to promote angiogenesis and metastasis. While it is appreciated that depletion of MDSCs could bring tumoricidal effects, there are significant gaps in knowledge about the underlying mechanisms responsible for MDSC recruitment to tumor sites. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of HCC that modifies the stromal components. Using hepatocellular carcinoma (HCC) as a model, we investigated whether hypoxia is a driver of MDSC recruitment in HCC.
Experimental Procedures: Gene profiling of HCC cells exposed to hypoxia and normoxia were analyzed by transcriptome sequencing to identify potential hypoxia-induced chemokines for MDSC recruitment. MDSCs were isolated from HCC-bearing mice by magnetic bead sorting for different functional assays. Boyden chambers were used to evaluate the invasive ability of MDSCs. Flow cytometry was used to detect the frequencies of tumor-associated MDSCs in orthotopic HCC mouse models.
Results: We observed that MDSCs preferentially infiltrated into hypoxic regions in human HCC tissues and hypoxia-induced MDSC infiltration was dependent on hypoxia-inducible factors (HIFs). HIFs activated the transcription of chemokine (C-C motif) ligand 26 (CCL26) in HCC cells to recruit chemokine (C-X3-C motif) receptor 1 (CX3CR1)-expressing MDSCs to the primary tumor. Knockdown of CCL26 in HCC cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of CCL26 production in HCC cells by HIF inhibitor, digoxin, or blockade of CX3CR1 in MDSCs by CX3CR1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth.
Conclusion: This study unprecedentedly reveals a novel molecular mechanism by which HCC cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against HCC.
Citation Format: David Kung-Chun Chiu, Iris Ming-Jing Xu, Robin Kit-Ho Lai, Aki Pui-Wah Tse, Larry Lai Wei, Hui-Yu Koh, Regina Cheuk-Lam Lo, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong. Hypoxia as a driver of myeloid-derived suppressor cell recruitment in hepatocellular carcinoma via CCL26/CX3CR1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4399.
Abstract 4401: Disclosing the Hippo signaling networks in castration-resistant prostate cancer
Authors: Ready Damien , Yildiz Yuksel , Funari Vincent , Bozdag Serdar , Cinar Bekir 
Published: July 2016

Abstract
Prostate cancer often evolves as a metastatic castration-resistant disease, which is lethal. Despite recent advances, the molecular mechanisms contributing to this lethal disease are largely unknown. Our initial studies have indicated that the loss-of-function of the STK4-encoded MST1 protein kinase, a key component of the Hippo tumor suppressor pathway, may play a prominent role in the etiology of prostate cancer progression. Here, we establish cytoplasmic-, membrane- or nuclear-localized MST1 cell models to elucidate a possible mode of actions by which MST1 control the disease progression. We show that membrane or nuclear MST1 confers superior growth inhibitory effects on castration-resistant prostate cancer cells ex vivo and in vivo in comparison with cytoplasmic MST1, though they express the similar levels of MST1 protein. Consistently, a number of differentially expressed genes (2-fold with FDR ≤ 0.05) regulated by membrane or nuclear MST1 protein are much greater than cytoplasmic MST1, as assessed by RNA-sequencing and bioinformatics analysis. Functional annotation clustering reveals that genes affected by cytoplasmic MST1 protein are mostly associated with cell-cell interactions and membrane trafficking. However, expression of genes altered by membrane or nuclear MST1 involves much broader cellular biology that includes cell signaling, steroid biogenesis, lipid and cholesterol metabolisms, and developmental processes. In addition, Ingenuity Pathway analysis indicates that several genes effected by ectopic MST1 protein the defined cell location interact with androgen receptor pathway signaling, a critical regulator of prostate cancer pathogenesis. The results of this study suggest that the Hippo pathway signaling restricts prostate cancer progression by modulating the array of signaling networks, indicating important therapeutic implications for human disease.
Citation Format: Damien Ready, Yuksel Yildiz, Vincent Funari, Serdar Bozdag, Bekir Cinar. Disclosing the Hippo signaling networks in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4401.
Abstract 4402: Glycosyltransferase ST6Gal-I enables cancer cells to survive upon growth factor deprivation
Authors: Britain Colleen , Bellis Susan 
Published: July 2016

Abstract
Tumor growth often outpaces the tumor's ability to form new vascularization leading to a tumor microenvironment containing areas with limited access to serum-derived growth factors (GFs). How tumor cells are able to proliferate and survive in the absence of GFs is not completely understood. Recent work from our group has uncovered a novel mechanism by which ST6Gal-I, a glycosyltransferase upregulated in many cancers, enables cells to evade GF deprivation-mediated apoptosis. ST6Gal-I is a trans-Golgi sialyltransferase that catalyzes the addition of a bulky, negatively charged sialic acid in an α2-6 manner to the termini of N-linked glycans on glycoproteins bound for the plasma membrane. This sialic acid addition can modulate protein conformation and function, similar to phosphorylation. Prior studies from our group show that ST6Gal-I activity confers a cancer stem cell phenotype as well as enhances chemoresistance, leading us to hypothesize that ST6Gal-I promotes tumor cell survival, invasion and metastasis. To better understand the role ST6Gal-I plays in tumor cell survival upon GF deprivation, we monitored the response of ovarian and pancreatic cancer cells with either ST6Gal-I overexpression or knockdown to serum starvation. Upon serum starvation, cells overexpressing ST6Gal-I preferentially survived and continued to proliferate whereas cells with ST6Gal-I knockdown underwent cell death more readily, as evidenced by live-dead cell staining and cell proliferation assays. Furthermore, in the absence of serum, ST6Gal-I activity promotes the activation and/or expression of multiple pro-survival proteins, such as Akt, p70-S6K, NFκB, and cIAP2, as well as cell cycle regulators including CyclinD2. Interestingly, upon long-term GF deprivation, immunoblotting analysis reveals a selective enrichment for ST6Gal-I in the remaining live cells providing evidence that cells with high ST6Gal-I expression selectively survive GF deficiency. Collectively these data suggest that upregulation of ST6Gal-I in tumor cells may promote cell survival in areas of the tumor microenvironment that have decreased access to a blood supply.
Citation Format: Colleen Britain, Susan Bellis. Glycosyltransferase ST6Gal-I enables cancer cells to survive upon growth factor deprivation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4402.
Abstract 4404: NFAT-5/STAT-3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer cells
Authors: Amara Suneetha , Alotaibi Dalal , Tiriveedhi Venkataswarup 
Published: July 2016

Abstract
Chronic inflammation has been considered an important player in cancer proliferation and progression. High salt (sodium chloride) has been considered a potent inducer of chronic inflammation. In this study, we investigated the synergistic role of high salt with IL-17 towards induction of inflammatory and angiogenic stress factor VEGF. Stimulation of MCF-7 breast cancer cells with high salt (0.2 M NaCl) and sub-minimal IL-17 (1 ng/mL) enhanced the expression of VEGF-A (2.9 and 2.6 fold, respectively p&lt;0.05) compared to untreated cells. Further, co-treatment with both high salt and sub-minimal IL-17 demonstrated a 5.9 fold increase in VEGF-A expression (p&lt;0.01), thus suggesting a synergistic role of these both factors. VEGF-A promoter analysis and specific siRNA knock-down of transcription factors revealed that high salt induces VEGF-A through NFAT5, while IL-17 induced VEGF-A via STAT-3 signaling mechanisms. Treatment of the supernatant from activated MCF-7 cells on normalized human aortic endothelial cells induced enhanced cell migration and expression of migration specific factors VCAM, β1-integrin and CD31. Based on these data, we conclude that high salt synergizes with pro-inflammatory IL-17 to potentially induce cancer progression and metastasis through VEGF-A expression. Therefore, low salt diet, anti-NFAT5 and anti-STAT3 therapies might provide novel venues for enhanced efficiency of current cancer therapy.
Citation Format: Suneetha Amara, Dalal Alotaibi, Venkataswarup Tiriveedhi. NFAT-5/STAT-3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4404.
Abstract 4413: Thrombospondin-1 is a master regulator of glioblastoma vascularization and infiltration
Authors: Daubon Thomas , Leon Celine , Clarke Kim , Poulet Mathilde , Miletic Hrvoje , Falciani Francesco , Bjerkvig Rolf , Bikfalvi Andreas 
Published: July 2016

Abstract
Glioblastoma are heterogeneous tumours composed of different subpopulations of cells with different behavioral characteristics. Areas of highly angiogenic cells co-exist with populations of non-angiogenic but highly invasive and infiltrative cells. This heterogeneity is a key clinical challenge in glioma treatment.
We used a large scale RNA sequencing approach to investigate the molecular components which differentiate infiltrative from angiogenic cells, in a Patient Derived Xenograft (PDX) mouse model. Our bioinformatic analysis revealed TGFβ1 to be a master regulator of tumor development, and Thrombospondin-1 (Tsp1) to be up regulated in infiltrative areas as compared to angiogenic area. Thrombospondins are known as anti-angiogenic factors, however the full roles of these multi domain proteins in tumor development remain to be elucidated.
We found Tsp1 expression to be upregulated in grade IV-GBM and in silico in the GBM mesenchymal subclass. It is expressed not only in tumor cells, but also in tumor blood vessel endothelial cells (ECs). TGFβ1 transcriptionally regulated Tsp1 via Smad1 and Smad3. However, contrary to previous results, we found that Tsp1 was not involved in TGFβ1-activation in tumor cells. We showed that Tsp1 regulates cell migration and invasion both in vitro and in vivo. Inhibition of Tsp1 expression in vivo correlated with increased tumor vascularization in both the chick CAM assay and the PDX mouse model.
Anti-angiogenic treatments in the PDX mouse model leads to increased tumor hypoxia and invasive tumor cell behavior, as described in our previous work. In this context, both TGFβ1 and Tsp1 were upregulated in tumor cells. Downregulation of tumor-derived Tsp1 by shRNA in the presence of anti-angiogenic therapy led to reduced tumor growth and invasion in vivo. Finally, peptide-mediated inhibition of Tsp1 activity demonstrated that Tsp1/CD47 interaction is involved in the invasive capacity of GBM cells.
Taken together, our data suggest that Tsp1 inhibition may be a promising therapeutic approach to limit tumor infiltration induced by treatment with anti-angiogenic agents.
Citation Format: Thomas Daubon, Celine Leon, Kim Clarke, Mathilde Poulet, Hrvoje Miletic, Francesco Falciani, Rolf Bjerkvig, Andreas Bikfalvi. Thrombospondin-1 is a master regulator of glioblastoma vascularization and infiltration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4413.
Abstract 4416: Combination of HSP90 and proteasome inhibitor is effective in pancreatic cancer
Authors: Nagaraju Ganji Purnachandra , Rajitha Balney , Benton Leah , El-Rayes Bassel F. 
Published: July 2016

Abstract
Background: Heat shock protein (HSP90) and proteasome play an important role in cellular protein trafficking and degradation in pancreatic cancer (PC). Given the overlap in the mechanism of action, we investigated the effects of the combination of pharmacological inhibitors of HSP90 (Ganetespib) and proteasome (Carfilzomib) on PC cells in vitro and in vivo.
Methods: The combined effects of ganetespib and carfilzomib were evaluated in MIA PaCa-2 and HPAC cell lines using a cell proliferation
assay. Effects on the expression of survival (PI3K/AKT, and ERK), cell cycle (Cdc-2 and cyclin B1), angiogenesis (HIF-1α and VEGF) and autophagy (LC3 A/B, and Atg7) pathways were examined by Western blot. Cell cycle analysis was performed by FACS assay. HPAC cell lines were tested for efficacy to ganetespib, carfilzomib, alone and in combination, using an in vivo tumor xenograft model.
Results: The combination of ganetespib and carfilzomib significantly decreased cell proliferation, induced G2-M cell cycle arrest and induced autophagy in both MIA PaCa-2 and HPAC cell lines. Ganetespib and carfilzomib also decreased the activation of ERK, PI3K/AKT, and autophagy signaling molecules (LC3 A/B, and Atg7). In animal models, ganetespib potentiated the effects of carfilzomib, as measured by tumor
volume. Western blot analysis from tumors removed from animals confirmed the effects of ganetespib and carfilzomib on survival, cell cycle, autophagy and angiogenesis.
Conclusion: These observations provide preclinical proof-of-principle that combinatorial targeting of HSP90 and proteasome is a rational approach for development in PC clinical trials.
Citation Format: Ganji Purnachandra Nagaraju, Balney Rajitha, Leah Benton, Bassel F. El-Rayes. Combination of HSP90 and proteasome inhibitor is effective in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4416.
Abstract 4419: Exploration of alternative pathways mediated by IFNL4 and related to cell proliferation and death in a hepatoma cell line
Authors: Wang Fang , Onabajo Olusegun O. , Rao Nina , Prokunina-Olsson Ludmila 
Published: July 2016

Abstract
The ability to generate interferon lambda 4 (IFNL4), the most recently discovered member of the type-III interferon family, has been associated with impaired clearance of hepatitis C virus (HCV). IFNL4 signals through an IFNL receptor complex that serves all type-III interferons and consists of receptors IFNLR1 and IL10R2. Signaling through IFNL receptor complex leads to activation of the JAK-STAT pathway and transcriptional activation of interferon-stimulated genes (ISG). Intracellular expression of IFNL4 also causes reduced proliferation and increased cell death in human hepatic cells but it remains unclear if this is a result of JAK-STAT signaling through IFNL receptor complex or through some other alternative mechanisms. To address this question, we used CRISPR-CAS9 system to knock-out IFNLR1 in a hepatoma HepG2 cells. We designed and tested six guide RNAs (gRNAs) for IFNLR1 exons. CAS9 protein and gRNAs that most efficiently induced mutations in IFNLR1 were introduced into HepG2 cells to generate stable cell lines. No obvious defects were observed in IFNLR1-KO-HepG2 cells, indicating that loss of IFNLR1 had no deleterious effects on cell viability. We selected three stable clones which had sequencing-confirmed inactivating IFNLR1 mutations and Western blot-confirmed lack of IFNLR1 protein expression. Compared to the parental HepG2 cells the IFNLR1-KO-HepG2 cells were deficient in the ability to induce the luciferase-tagged interferon-stimulated response element (ISRE-Luc) reporter after treatment with recombinant IFNL4 and IFNL3 proteins, which signal through the same receptor complex. At the same time, response to IFNa treatment was not affected because IFNa signals through its own receptor complex. These results indicate that, as other type-III interferons, IFNL4 induces ISRE signaling through IFNL receptor complex. INFLR1-KO-HepG2 cells provide a highly efficient model for studies of factors involved in signaling of type-III interferons, including IFNL4. Next, we will investigate alternative pathways involved in anti-proliferative and cell death-related phenotypes induced by IFNL4 in HepG2 cell. We will perform RNA-seq on parental and IFNLR1-KO-HepG2 cells treated with or without IFNL4, IFNL3 and IFNa. These results will contribute to a better understanding of IFNL4 function, which can be relevant for viral infections and cancer.
Citation Format: Fang Wang, Olusegun O. Onabajo, Nina Rao, Ludmila Prokunina-Olsson. Exploration of alternative pathways mediated by IFNL4 and related to cell proliferation and death in a hepatoma cell line. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4419.
Abstract 4424: Acetylation of Fascin on the lysine 471 residue produces a change in growth and mobility phenotype of esophageal cancer cells by inducing F-actin rearrangement
Authors: Zeng Fa-Min , Wang Xiao-Ning , Zhang Ying-Li , Liao Lian-Di , Li En-Min , Xu Li-Yan 
Published: July 2016

Abstract
Elevated expressions of fascin mRNA and protein in cancer cells have been correlated with aggressive clinical course, poor prognosis and shorter survival. Fascin is an evolutionarily conserved actin-binding protein that plays a key role in forming filopodia. It is reported that the lysine 471 residue (K471) of fascin can be acetylated and also involves in its actin binding, but the roles of K471 acetylation in filopodia formation are still uncertain. In this paper, we produced point mutants mimicking the active deacetylated (Lys471Arg, K471R) or inactive acetylated (Lys471Gln, K471Q) states of fascin. The actin-binding assay showed that the fascin K471Q mutation decreased the actin binding activity of fascin, compared with wild-type fascin (WT) and K471R mutant fascin in the esophageal cancer cells. Moreover, live imaging revealed that K471Q mutant fascin reduced the number and length of filopodia, whereas the K471R mutant increased filopodia frequency. The fascin K471Q mutation changed the straight filopodia became forniciform filopodia. The protrusion presented abnormal morphology when cells spread. Further functional experiments showed that the K471Q mutant fascin rendered the tumor cell migration, invasion and tumorigenesis decrease significantly, whereas K471R mutant fascin like WT fascin still maintained a strong ability. Taken together, we propose that the lysine K471 residue may be a key specific actin crosslinking site and also involved in the tumor biological function of fascin.
Citation Format: Fa-Min Zeng, Xiao-Ning Wang, Ying-Li Zhang, Lian-Di Liao, En-Min Li, Li-Yan Xu. Acetylation of Fascin on the lysine 471 residue produces a change in growth and mobility phenotype of esophageal cancer cells by inducing F-actin rearrangement. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4424.
Abstract 443: Prognostic significance of CXCL12 protein levels in high-grade serous ovarian carcinoma
Authors: Buisseret Laurence , Delisle Vincent , Communal Laudine , Pommey Sandra , Stagg John 
Published: July 2016

Abstract
Signals mediated by the C-X-C chemokine ligand 12 (CXCL12; stromal-derived factor 1) and its receptor CXCR4 have been implicated in cancer progression through multiple tumorigenesis processes, including cancer cell proliferation, survival, invasion and tumor angiogenesis. In vitro and murine models recently demonstrated that this axis is also involved in the mechanism of tumor immune evasion and resistance to immune checkpoint inhibitors. In human ovarian cancer, this axis has been associated with ascites, nodes and peritoneal metastasis.
We investigated the prognostic value of CXCL12 protein expression and association with CD8+ T cell infiltration in a cohort of 203 patients diagnosed with a high-grade serous ovarian carcinoma (HGSC). Quantitative immunofluorescence allowed us to evaluate the frequency and level of expression of CXCL12 and CD8+ cell density in the epithelial and stromal tumor compartments. CXCL12 expression in the epithelial tumor compartment was significantly higher than in the stromal compartment (p&lt;0.0001). Strikingly, high levels of tumoral CXCL12 expression were significantly associated with a worse progression-free survival (PFS) and overall survival (OS) (log-rank test, p = 0.007 & p = 0.006, respectively). The Kaplan-Meier median PFS and OS were respectively of 17±1.5 and 42±6.9 months in patients with high levels and of 18±3.6 and 61±7.5 months in patients with low levels of CXCL12. Notably, multivariate analysis showed that CXCL12 levels were associated with a worse outcome independent of FIGO stage and residual disease. No correlation was observed between CXCL12 expression levels and CD8+ T cell density. Intriguingly, in CD8+ subgroup analyses, the prognostic value of CXCL12 levels was restricted to tumors with low intraepithelial CD8+ T cell densities.
Flow cytometry and quantitative real-time PCR results suggest that CXCL12 promotes a mesenchymal phenotype and increased expression of cancer stem cells markers on human ovarian cancer cells.
In conclusion, modulation of the CXCL12/CXCR4 axis is a promising approach in HGSC that may potentiate immunotherapies and may act on epithelial-to-mesenchymal transition. Our study highlights the rationale to evaluate in the clinical setting treatments targeting the CXCL12/CXCR4 in HGSC, specifically in patients lacking CD8+ T cell tumor infiltration.
Citation Format: Laurence Buisseret, Vincent Delisle, Laudine Communal, Sandra Pommey, John Stagg. Prognostic significance of CXCL12 protein levels in high-grade serous ovarian carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 443.