bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1968: Tumor necrosis factor-α upregulation of CCR7 induces prostate cancer cell migration in lymphatic metastasis
Authors: Makino Tomoyuki , Izumi Kouji , Maolake Aerken , Natsagdorj Ariunbold , Iwamoto Hiroaki , Kadomoto Suguru , Naito Renato , Hiratsuka Kaoru , Kadono Yoshifumi , Mizokami Atsushi 
Published: August 2019

Abstract
Objectives: Prostate cancer (PCa) with lymph node (LN) metastasis has a poor patient prognosis. Broader understanding of the causes of LN metastasis and disease dissemination will assist in developing novel treatments. C-C chemokine receptor 7 (CCR7) and its ligand CCL21 are abundantly expressed in LN metastasis and during PCa progression. Tumor necrosis factor-alpha (TNF-α) is present at low levels within the tumor microenvironment. TNF-α and C-C chemokines interact in tumorigenesis. The study aim was to determine whether TNF-α might promote PCa dissemination from metastatic LN by activating the CCL21/CCR7 axis.
Methods: TNF-α and CCR7 mRNA and protein expression were assayed in PC-3, DU145, and LNCaP, and human PCa cells by reverse transcription-polymerase chain reaction and western blotting. Promotion of transmembrane migration by TNF-α was assayed in CCL21-pretreated PCa cells. Phosphorylation of several mitogen-activated protein kinases expressed downstream of TNF-α was assayed.
Results: Low-dose TNF-α induced CCR7 expression in PCa cells and promoted migration of CCL21-pretreated PCa cells. TNF-α-mediated CCR7 upregulation via the ERK signaling pathway. p38 was a downstream target of CCL21/CCR7 signaling and a key factor in the promotion of PCa cell migration.
Conclusions: This is the first demonstration of the influence of the TNF-α-CCL21/CCR7 axis on PCa cell migration in the microenvironment of LN metastasis. Because it is activated in PCa LN metastasis, the CCL21/CCR7 axis might be a novel therapeutic target and biomarker of PCa.
Citation Format: Tomoyuki Makino, Kouji Izumi, Aerken Maolake, Ariunbold Natsagdorj, Hiroaki Iwamoto, Suguru Kadomoto, Renato Naito, Kaoru Hiratsuka, Yoshifumi Kadono, Atsushi Mizokami. Tumor necrosis factor-α upregulation of CCR7 induces prostate cancer cell migration in lymphatic metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1968.
Abstract 1972: CXCR5-CXCL13 signaling contributes to CLL relapse and patient survival
Authors: Griffen Tiara , Young Corey , Dill Courtney D. , Carey Kaylin , Adebayo Olayinka , Nunez Sha'kayla , Lillard James 
Published: August 2019

Abstract
Chronic Lymphocytic Leukemia (CLL) is characterized by the appearance of mature-appearing B cells in the blood, bone marrow, and secondary lymphoid organs. There is an average of 19,000 new cases, in the United States annually, but the molecular pathogenesis of CLL is incompletely understood. Chemokines and their receptors have been shown to contribute to the progression and metastasis of several types of cancers. Chemokine receptor 5 (CXCR5) and chemokine ligand 13 (CXCL13) are produced by cells in the microenvironment of secondary lymphoid organs such as lymphatic endothelial cells, which promote disease progression. There is a gap in understanding the molecular mechanisms and functions resulting from CXCL13-CXCR5 interactions during CLL. This gap is important to fill, because these molecules could be additional therapeutic targets to treat this disease. Together this provided the rationale to test the hypothesis CXCR5-CXCL13 signaling contributes to the growth, metastasis, and survival of CLL. The role of CXCR5, CXCL13, and associated genes was determined by conducting Weighted Gene Network Co-expression (WGCNA) and upstream regulator, canonical pathway, and gene interaction analyses of 297 International Cancer Genome Consortium (ICGC) CLL patients. Our previous studies show CXCR5-CXCL13 signaling activates CTNNB1, JUN, and VAV2 transcriptional factors. These factors promote the expression of GNA, GRK, PIK3, RAC and RHO family genes, which were significantly associated with the WGCNA-designated Yellow signaling module. Interestingly, the WGCNA-designated Grey module contained independently expressed genes, e.g., CXCL13, LTB, IGHV, ZAP70, which were significantly associated (p = 0.00003) and correlated (R2 = 0.29) with relapse. Genes in this module significantly correlated with CLL relapse and survival. Taken together, our data demonstrate the clinical significance of the CXCL13-CXCR5 pathway in CLL progression.
Citation Format: Tiara Griffen, Corey Young, Courtney D. Dill, Kaylin Carey, Olayinka Adebayo, Sha'kayla Nunez, James Lillard. CXCR5-CXCL13 signaling contributes to CLL relapse and patient survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1972.
Abstract 1977: Chemokines expression in an in vitro model of melanoma brain metastasis
Authors: Santos Renata , Sampaio Maria Clara , Albuquerque Amanda , Pereira Michelly , Pitta Maira , Rêgo Moacyr 
Published: August 2019

Abstract
Melanoma brain metastasis is still a great challenge. This work aimed to characterize the secretion profile and understand the possible role of chemokines in a xenogeneic in vitro model of melanoma brain metastasis. Brain primary mixed cultures from cerebral cortex were prepared from the neonates Wistar rats and maintained at 37°C, 5% CO2until 80% of confluency and maturity. Melanoma lineages used were UACC62 and SKMEL-28. Co-cultures were performed to study the direct interactions between melanoma and cortical cells. The indirect effects in the cerebral microenvironment were evaluated through conditioned medium (CM) from brain cells on melanoma lineages. It was used an early CM collected at 24h (CM24) and a late CM collected after 48h (CM48), whose both were incubated during more 24h (24CM24 and 24CM48) or 48h (48CM24 and 48CM48) on melanoma cultures. The chemokines IP10, CCL5 and IL8 were studied through Cytometric Bead Array (CBA),MIG and CCL2 also, however their values were undetectable. After the characterization of the model, IP10 was silenced to evaluate its influence in the model. CBA demonstrated that in SKMEL-28 the late soluble factors during 48h (48CM48) were capable of rase IP10 levels (p=0,0286). On the other hand, direct and indirect contact with brain cells reduced IL8 levels, compared to SKMEL28 alone with respectively p = 0.02 and p=0,0286, where both chemokines were not detected. On UACC62, IP10 levels were higher only in the co-culture (p=0,02), suggesting the need of contact between the different cells. Also, IL8 was decreased in all conditions compared to UACC62. After IP10 silencing, SKMEL-28 presented higher levels of IL8 in 48CM48. On UACC62, the IP10 silencing resulted in elevation of IL8 levels when the cells were in co-culture. RANTES did not present alterations in its levels in any of the conditions after IP10 knock-down. The IP10 silencing was also capable of impair the transwell invasion of SKMEL-28 in the presence of CM24 and CM48. Together, these results confirmed that IP10 alters IL8 levels, but no RANTES in a mimetic microenvironment of melanoma brain metastasis. Furthermore, IP10 is capable of influencing SKMEL-28 migration in this xenogeneic model. More studies to better understand the role of IP10 and IL8 in the establishment of melanoma brain metastasis in this model are in progress.
Citation Format: Renata Santos, Maria Clara Sampaio, Amanda Albuquerque, Michelly Pereira, Maira Pitta, Moacyr Rêgo. Chemokines expression in an in vitro model of melanoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1977.
Abstract 1978: Sarcoma invasion associated with heparan sulfate degradation
Authors: Ju Donghong , Lipovich Leonard , Kosir Mary A. 
Published: August 2019

Abstract
INTRODUCTION: Sarcomas are locally aggressive, angiogenic and spread hematogenously. The purpose of this study was to quantify the effect of heparan sulfate degrading activity on invasion of K-ras-transformed sarcoma cells.
METHODS: Heparan degrading enzyme assays were performed in triplicate on lysate from Balb/c 3T3 (fibroblasts) and K234 cells (K-ras-transformed 3T3) cells (sarcoma) using an enzyme assay kit (cat# MK412;Takara). Invasion assays were performed using Corning Matrigel Invasion Chamber (cat#354480; ThermoFisher ). 7.5 x 104 cells were placed in serum-free DMEM in the upper chamber (insert), and DMEM with 10% FBS as attractant in the lower chamber. After incubation for 24 h at 37 °C, the insert was removed and cells on the undersurface of the insert were fixed with 5% glutaraldehyde for 10 min, then stained with 1% crystal violet in 2% ethanol for 20 min. After the insert was dry, the cells on the filter were counted by microscope over multiple fields. For experiments with inhibitors, 10 ug/ml λ-carageenan (cat# 22049; Sigma), anti-NAP-2 antibody (cat# sc-19224; Santa Cruz Biotech), or anti-HPA1 antibody were used.
RESULTS: Heparan sulfate-degrading activity was 0.0625 U/ug for K234 cell lysate compared to 0.0125 U/ug for Balb/c3T3 cells. λ-carageenan inhibited the activity completely confirming glycanase inhibition. Anti-NAP2 and anti-HPA1 antibody inhibited heparan sulfate degrading activity in 3T3 lysate. Invasion was two-fold greater by K234 cells than for 3T3 cells. When anti-NAP2 antibody was added to the invasion assay, both K234 and 3T3 cell invasion was inhibited by 55% and 54%, respectively. Less than 1% inhibition of invasion occurred with anti-HPA1 antibody.
CONCLUSION: The invasion of heparan sulfate-containing Matrigel by K234 cells is partly influenced by heparan sulfate-degrading activity. The inhibition of the degrading activity by an anti-chemokine antibody decreased invasion, and invokes other processes for the malignant sarcoma phenotype.
Citation Format: Donghong Ju, Leonard Lipovich, Mary A. Kosir. Sarcoma invasion associated with heparan sulfate degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1978.
Abstract 1983: Cancer exosomes immunosuppressive activity in the absence of contaminating soluble factors is multifactorial
Authors: Shu Shin La , Matsuzaki Junko , Allen Cheryl , Yang Yunchen , Hurley Edward , Odunsi Kunle , Wu Yun , Ernstoff Marc S. 
Published: August 2019

Abstract
Cancer derived exosomes, along with soluble factors such as growth factors, cytokines and chemokines have been identified as integral immunosuppressive pathways employed by cancer cells. Using melanoma cell lines as a model for generating human melanoma exosomes (HMEX), we studied the soluble factors associated with exosome purification methods. A Luminex 13-plex T cell activation kit was used to detect the presence of soluble factors in exosome isolates. We have demonstrated that combining Ultrafiltration and Size Exclusion Chromatography (REIUS method) can yield up to 58-fold more exosomes than ultracentrifugation (UC) with greatly reduced concentrations of contaminating soluble factors (IL-8: 4.6 pg/ml by REIUS versus 489 pg/ml by UC | IL-10: 1,052 pg/ml by REIUS versus 34,500 pg/ml by UC). A novel exosome-based Compact Surface Plasmon Resonance Biosensor demonstrated that REIUS-isolated exosomes abundantly express PD-L1 on their surface compared to UC-purified exosomes. These HMEX significantly inhibited a cloned NY-ESO tumor antigen-specific patient derived T cell function when co-cultured with a NY-ESO positive melanoma cell line for 4 h (IFN-γ positive T cell population: 78.5 ± 0.03 % versus 49.05 ± 0.07 %). Blocking with anti-PDL1 or anti-IL-10 failed to restore T cell function (IFN-γ production), while both anti-PD-L1 and anti-IL-10 antibodies partially reverse this suppression, thereby identifying IL-10 and PD-L1 as a novel collaborating inhibitory pathway. Taken together, we report that different exosome isolation methods impact the nature of the exosomes and contaminating soluble factors and should be chosen with caution. In addition, our data suggests a novel role for tumor-derived exosomes in the IL-10 and PD1-PDL1 axis crosstalk that impacts functional activity of T cells.
Citation Format: Shin La Shu, Junko Matsuzaki, Cheryl Allen, Yunchen Yang, Edward Hurley, Kunle Odunsi, Yun Wu, Marc S. Ernstoff. Cancer exosomes immunosuppressive activity in the absence of contaminating soluble factors is multifactorial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1983.
Abstract 1986: Breast cancer-secreted exosomes stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumor progression
Authors: Li Juanjuan , Wu Qi , Li Zhiyu , Sun Si , Zhu Shan , Wang Lijun , Wu Juan , Zhang Yimin , Yuan Jingping , Sun Shengrong , Wang Changhua 
Published: August 2019

Abstract
Background: Emerging evidence supports the pivotal roles of adipocytes in breast cancer progression. Beige/brown adipose tissue that activates thermogenesis is suggested to contribute to the hypermetabolic state. However, the mediators and mechanisms remain unclear.
Methods: Survival probabilities for recurrence-free survival (RFS) of 106 breast cancer patients were estimated using the Kaplan-Meier method based on the immunohistochemistry results of several biomarkers. Biochemical studies were performed to characterize the novel interrelation between breast cancer cells and adipocytes.
Results: In the survival analysis, high MCT4 expression in stromal adipose tissue and overexpression of CD36 or FATP1 in malignant tissue predict poor prognosis for breast cancer patients. We show that tumor-surrounding adipocytes exhibit an altered phenotype in terms of upregulated beige/brown characteristics and increased catabolism. This increase in catabolism is associated with an activated state characterized by the release of metabolites, including free fatty acids, pyruvate, lactate and ketone bodies. Likewise, tumor cells cocultivated with mature adipocytes exhibit metabolic adaptation and an aggressive phenotype in vitro and in vivo. Mechanistically, we show that tumour cells induce beige/brown differentiation and remodel metabolism in resident adipocytes by secreting exosomes that carry high levels of miRNA-144 and miRNA-126. Cancer cell-secreted miRNA-144 promotes beige/brown adipocyte characteristics by downregulating the MAP3K8/ERK1/2/PPARγ axis. We also found that exosomal miRNA-126 remodels metabolism by disrupting IRS/Glut-4 signalling, activating the AMPK/autophagy pathway and stabilizing HIF1α expression in imminent adipocytes. In vivo inhibition of miRNA-144 or miRNA-126 decreases adipocyte-induced tumour growth.
Conclusions: These results demonstrate that cancer-derived exosomal miRNA-144 and miRNA-126 can reprogram the systemic energy metabolism to facilitate tumor progression by inducing beige/brown differentiation and enhancing catabolism in recipient adipocytes.
Citation Format: Juanjuan Li, Qi Wu, Zhiyu Li, Si Sun, Shan Zhu, Lijun Wang, Juan Wu, Yimin Zhang, Jingping Yuan, Shengrong Sun, Changhua Wang. Breast cancer-secreted exosomes stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1986.
Abstract 1990: Cjc-1134-pc, a long-acting glp-1r agonist, effects in modulating pro-inflammatory cytokines in the tumor environment
Authors: Liu Xiping , Hong Sean , Wu Shijuan , Yao Zhiwen , Xie Qiang 
Published: August 2019

Abstract
The incidence rates of The incidence rates of diabetes and cancer are growing globally. It is reported that type 2 diabetes (T2D) is associated with increased risk of cancers, which suggests a synergy. There is a strong association among inflammation and cancer on diabetes, which is reflected by the high cytokine prevalence in the microenvironment. Previously our studies showed that IL-2 and IFN-γ were downregulated but IL-6 and TNFα were upregulated in diabetic mice. The levels of IL-2, IFN-γ, IL-6 and TNFα returned to baseline levels similar to that of non-diabetic mice after the treatment of CJC-1134-PC. In order to explore the benefits of CJC-1134-PC beside its glucose lowering effects, the level of pro-inflammatory cytokines has been measured and compared between vehicle and CJC-1134-PC treated BALB/c mice bearing CT26 colon tumors. All mice bearing tumors showed high IL-6 and TNF-r compared with the normal mice. Interestingly, after CJC-1134-PC treatment, IL-6 and TNFα levels decreased significantly (P &lt; 0.05), which makes the cytokine profile close to the reported levels in normal mice. Overall, the data suggests that CJC-1134-PC plays a role in modulating inflammation, which could benefit cancer treatment in addition to achieving glycemic control.
Citation Format: Xiping Liu, Sean Hong, Shijuan Wu, Zhiwen Yao, Qiang Xie. Cjc-1134-pc, a long-acting glp-1r agonist, effects in modulating pro-inflammatory cytokines in the tumor environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1990.
Abstract 1993: Gluthathione peroxidase 2 downregulation in the PyMT mammary tumor model leads to an aggressive phenotype due to stimulation of angiogenesis and tumor stemness via HIF1 alpha signaling
Authors: Ren Zuen , Liang Huizhi , Benard Outhiriaradjou , Suyama Kimita , Albanese Joseph M. , Norton Larry , Zheng Wei , Hazan Rachel B. 
Published: August 2019

Abstract
Breast tumors are known to undergo high levels of mitochondrial oxidative phosphorylation leading to accumulation of reactive oxygen species (ROS), which in turn potentiate cancer stem cells and chemoresistance. This was shown to be due to HIF1α stabilization by ROS; however, the signaling events downstream of HIF1α regulating the cancer stem cell (CSC) phenotype remain unknown. Kaplan Meier survival curves upon the gene profiling database of breast cancer patients showed that reduced levels of the ROS scavenging enzyme, glutathione peroxidase 2 (GPx2) in breast cancers was associated with shorter patient survival duration. Consistent with this idea, we found that GPx2 was downregulated in metastatic mammary tumor cells, suggesting GPx2 loss enhances metastasis. Indeed, GPx2 knockdown in poorly metastatic cells increased ROS production, shortened tumor latency, and stimulated dramatic mammary tumor growth and metastasis. These effects were associated with marked increases in angiogenesis, CSC-like properties, and chemoresistance. Here, we show that GPx2 downregulation in mammary epithelial cells increases ROS production and HIF1α stabilization which were accompanied by VEGF upregulation and enhanced angiogenesis. On the other hand, GPx2 loss caused dramatic mammosphere formation and resistance to doxorubicin, implying effects on stemness leading to chemoresistance. These data suggest that GPx2 loss is a critical event that drives mammary tumorigenesis and metastasis via HIF1α signaling leading to stimulation of angiogenesis and stemness properties. Understanding the ramifications of GPx2 loss in breast cancer will allow us to identify key regulators of stemness and chemoresistance, with the goal of identifying novel drug targets in metastasis.
Citation Format: Zuen Ren, Huizhi Liang, Outhiriaradjou Benard, Kimita Suyama, Joseph M. Albanese, Larry Norton, Wei Zheng, Rachel B. Hazan. Gluthathione peroxidase 2 downregulation in the PyMT mammary tumor model leads to an aggressive phenotype due to stimulation of angiogenesis and tumor stemness via HIF1 alpha signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1993.
Abstract 2: Discovery of BAY 2402234 by phenotypic screening: A human Dihydroorotate Dehydrogenase (DHODH) inhibitor in clinical trials for the treatment of myeloid malignancies
Authors: Gradl Stefan N. , Mueller Thomas , Ferrara Steven , Sheikh Sherif El , Janzer Andreas , Zhou Han-Jie , Friberg Anders , Guenther Judith , Schaefer Martina , Stellfeld Timo , Eis Knut , Kroeber Michael , Nguyen Duy , Merz Claudia , Niehues Michael , Stoeckigt Detlef , Christian Sven , Zimmermann Katja , Lejeune Pascal , Bruening Michael , Meyer Hanna , Puetter Vera , Scadden David T. , Sykes David B. , Seidel Henrik , Eheim Ashley , Michels Martin , Haegebarth Andrea , Bauser Marcus 
Published: August 2019

Abstract
DHODH is a key enzyme in the biosynthesis of pyrimidines and recent studies have renewed interest in this old anti-cancer target. Here, we disclose the discovery of 4-triazolosalicylamides as inhibitors of DHODH and their structure activity relationship (SAR). The hit cluster was discovered during a phenotypic high throughput screen (HTS) of 2.5 million compounds where proliferation of H460 lung cancer cells was used as read-out. DHODH was successfully identified as the molecular target by comparing the activity profile of the hits in a panel of cell lines to a set of inhibitors with known pharmacological activity. The hit compounds showed good cellular potency but had undesirable DMPK properties. Interestingly, the compounds are non-ionizable in contrast to many other DHODH inhibitors and show no potency shift from biochemical to cellular assays. Structural modifications lead to compounds with sub-nanomolar potency in cellular assays and increased metabolic stability enabling the proof of concept in vivo xenograft experiments. Further optimization guided by lipophilicity efficiency and identification of metabolic hot spots resulted in molecules with low clearance and improved solubility. BAY 2402234 was selected as the clinical candidate after side by side comparison of a number of promising compounds. It shows great oral bioavailability, target engagement in all preclinical species tested, induces differentiation in AML models, and has excellent activity in a variety of leukemia models. A clinical phase I study has been initiated in patients with myeloid malignancies. (NCT03404726)
Citation Format: Stefan N. Gradl, Thomas Mueller, Steven Ferrara, Sherif El Sheikh, Andreas Janzer, Han-Jie Zhou, Anders Friberg, Judith Guenther, Martina Schaefer, Timo Stellfeld, Knut Eis, Michael Kroeber, Duy Nguyen, Claudia Merz, Michael Niehues, Detlef Stoeckigt, Sven Christian, Katja Zimmermann, Pascal Lejeune, Michael Bruening, Hanna Meyer, Vera Puetter, David T. Scadden, David B. Sykes, Henrik Seidel, Ashley Eheim, Martin Michels, Andrea Haegebarth, Marcus Bauser. Discovery of BAY 2402234 by phenotypic screening: A human Dihydroorotate Dehydrogenase (DHODH) inhibitor in clinical trials for the treatment of myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2.