bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1063: A clear cell renal cancer metastasis model identifies novel mediators of tumor aggressiveness and predictors of patient survival
Authors: Geist Felix , Dolt Teresa , Höfner Thomas , Klein Corinna , Vogel Vanessa , Stenzinger Albrecht , Holland-Letz Tim , Kossi Ornella , Weichert Wilko , Schirmacher Peter , Pahernik Sascha , Hohenfellner Markus , Trumpp Andreas , Sprick Martin 
Published: August 2018

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma with a 5-year survival rate of only 10.5%, and chemotherapy and radiotherapy regimen have shown limited efficacy. On the molecular level, significant inter- and intra-tumor heterogeneity hamper identification of drug targets, biomarkers and unraveling of disease mechanisms.
We developed a novel patient-derived model system of ccRCC that recapitulates the heterogeneity of the originating cancer enabling us to study ccRCC on a functional level. In five rounds and in three biological replicates of an in vivo selection, we transplanted the metastases of orthotopically transplanted tumor cells into the renal capsules of NOD scid gamma (NSG) mice. The tumor was enriched for cells with higher growth and metastatic potential compared to the initial heterogeneous population. Comparative gene-expression analysis revealed candidate genes associated with enhanced malignant growth and metastasis. Absolute shrinkage and selection operator (LASSO) regression identified a gene signature that can robustly predict patient survival. The prognostic power of our signature was additionally verified in independent patient cohorts suggesting that this approach leverages efficient stratification of patients into distinctive risk groups.
One of the hallmark genes in this signature is known to alter cellular signaling properties. Therefore, we hypothesized that this gene contributes to tumor growth and metastasis and thus to aggressiveness of ccRCC. In fact, in knockdown and overexpression xenografts experiments we could confirm an essential role for tumor aggressiveness in vivo suggesting that the gene and associated downstream signaling pathways are attractive targets for treatment of clear cell renal cancer.
Citation Format: Felix Geist, Teresa Dolt, Thomas Höfner, Corinna Klein, Vanessa Vogel, Albrecht Stenzinger, Tim Holland-Letz, Ornella Kossi, Wilko Weichert, Peter Schirmacher, Sascha Pahernik, Markus Hohenfellner, Andreas Trumpp, Martin Sprick. A clear cell renal cancer metastasis model identifies novel mediators of tumor aggressiveness and predictors of patient survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1063.
Abstract 1068: LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals
Authors: Chang Jae Won , Koo Bon Seok 
Published: August 2018

Abstract
Laminin subunit beta-3 (LAMB3) encodes one of the three subunits of LM-332, a protein of the extracellular matrix secreted by cultured human keratinocytes. While LAMB3 is involved in the invasive and metastatic abilities of several tumor types, including those found in the colon, pancreas, lung, cervix, stomach, and prostate, its mechanism of action in thyroid cancer has not been investigated previously. Our results show that LAMB3 is upregulated in papillary thyroid cancer, and that its suppression reduces cell migration/invasion via downregulation of epithelial–mesenchymal transition-associated proteins (N-cadherin, vimentin, slug) and inhibition of matrix metalloproteinase 9. LAMB3 suppression also significantly decreases Akt phosphorylation and inhibits the transcription of c-MET, reducing its activation. These results suggest that LAMB3 leads to tumor invasion via Akt activation induced by the HGF/c-MET axis in papillary thyroid cancer cells. Our findings reveal a novel mechanism of action for LAMB3 in papillary thyroid cancer cells.
Citation Format: Jae Won Chang, Bon Seok Koo. LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1068.
Abstract 1082: Loss of desmoglein 2 promotes tumor growth and progression through the activation of Src and facilitates the internalization of EGFR in biliary tract carcinoma cells
Authors: Lee Sang-Hyun , Min Jeong-Ki 
Published: August 2018

Abstract
Understanding the molecular carcinogenesis pathways is critical to establish novel individualized molecular targeted therapies and finally to improve overall clinical outcomes of patients with a highly heterogeneous group of malignancies such as biliary tract cancers (BTCs). In this context, we investigated the patho-physiological roles of a desmosomal component, desmoglein 2 (Dsg2) and found that Dsg2 functions as a tumor suppressor protein in BTC, as Dsg2 loss induced a number of cellular biological activities including proliferation, motility, invasion, transendothelial migration in vitro and tumor growth and metastasis in vivo. Clinico-pathological analyses of BTC patients indicated that lower expression of Dsg2 is associated with a poor prognosis of patients as perineural and lymphatic invasion were highly increased in those patients. In addition, loss of Dsg2 showed a significant increase of EGFR clearance from the cell membrane in BTC cells and patients' tumor tissues. Those cells were significantly decreased in the EGF-driven activation of EGFR and highly resistant to the anti-EGFR antibody treatment. Src appears to be involved in the Dsg2-mediated clearance of EGFR, as this significantly blocked by the suppression of cSrc expression in Dsg2-depleted cells, possibly through the direct binding of Dsg2 preferentially with an inactive form of Src through its SH2 domain. Suppression of cSrc by Src inhibitors or siRNA dramatically reduced BTC tumor growth in vitro and in vivo. In comparison with the anti-EGFR antibody therapy, Src-targeted therapies produced consistent anti-tumor activities independent with the expression status of EGFR in the BTC tumors. In conclusion, targeting Src would be a promising therapeutic approach to patients with advanced BTC and potentially useful in overcoming resistance to current anti-EGFR therapies, although further clinical studies are essentially required to translate the current preclinical knowledge into clinical practice.
Citation Format: Sang-Hyun Lee, Jeong-Ki Min. Loss of desmoglein 2 promotes tumor growth and progression through the activation of Src and facilitates the internalization of EGFR in biliary tract carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1082.
Abstract 1089: Role of high mobility group A2 (HMGA2) in prostate cancer
Authors: Hawsawi Ohuod A. , Burton Liza , Dougan Jodi , Millena Ana Cecillia , Nagappan Peri , Khan Shafiq , Odero-Marah Valerie 
Published: August 2018

Abstract
Prostate cancer is the most highly diagnosed cancer in men and the second leading cause of death in the United States. Epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. High mobility group A (HMGA2), a non-histone protein, has been shown to promote EMT in separate studies. Interestingly, wild-type HMGA2 and truncated (lacking the 3'UTR) HMGA2 isoforms are overexpressed in many cancers, but have not been investigated in prostate cancer. Jun-D is a transcriptional factor that might be regulated by HMGA2. Moreover, the function for each individual isoform is still not well understood. We hypothesize that each of the two isoforms of HMGA2 in will have different functions in prostate cancer. We stably overexpressed wild-type HMGA2 and truncated HMGA2 in LNCaP cells and measured the expression and the localization of EMT markers. We also measured reactive oxygen species (ROS) levels using DCFDA dye, since ROS has been associated with EMT. We performed migration and cell viability assays as well as Jun-D knockdown, a putative downstream effector of HMGA2. Our results showed that the overexpression of HMGA2 in LNCaP cells led to an increase in cell viability and migration for both wild-type and truncated HMGA2. We observed that wild-type, but not truncated HMGA2 promoted EMT. Additionally, Jun-D and ROS levels increased for truncated, but not significantly for wild-type HMGA2. Jun-D knockdown with siRNA decreased ROS and cell migration in cells with truncated HMGA2, but not in cells overexpressing wild-type HMGA2. Therefore, wild-type HMGA2 is the isoform that induces EMT, while the truncated form appears to have an alternate role in upregulating ROS via Jun-D. In conclusion, we show a link between HMGA2 and JunD/ROS for the first time, and data that wild-type and truncated HMGA2 may have differing functions that converge to increase cell proliferation and migration, and may in future instruct on more precise therapeutic targeting in patients with these isoforms.
GRANT SUPPORT: NIH 1P20MD002285 and NIH/NCRR/RCMI G12RR003062-22
Citation Format: Ohuod A. Hawsawi, Liza Burton, Jodi Dougan, Ana Cecillia Millena, Peri Nagappan, Shafiq Khan, Valerie Odero-Marah. Role of high mobility group A2 (HMGA2) in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1089.
Abstract 1101: Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer network in vitro and in vivo
Authors: Tazawa Hiroshi , Ieda Takeshi , Yano Shuya , Kikuchi Satoru , Kuroda Shinji , Ohara Toshiaki , Noma Kazuhiro , Kishimoto Hiroyuki , Nishizaki Masahiko , Kagawa Shunsuke , Saitou Takashi , Imamura Takeshi , Fujiwara Toshiyoshi 
Published: August 2018

Abstract
Background: Epithelial-mesenchymal transition (EMT) is a biologic process by which epithelial cancer cells acquire mesenchymal phenotype with malignant properties for invasion and metastasis, leading to poor prognosis. Inflammatory microenvironment has been shown to be responsible for the development and progression of colorectal cancer (CRC). However, the precise role of inflammatory microenvironment in the EMT-related tumor progression remains unclear because EMT network is regulated by complex crosstalk between tumor and normal cells. In this study, we developed a fluorescence-guided live-cell imaging system for the spatiotemporal visualization of EMT state, and assessed the in vitro and in vivo visualization of EMT state in human CRC cells under the inflammatory microenvironment.
Methods: We used two human CRC cell lines, HCT116 and RKO. The promoter of mesenchymal marker vimentin was used for inducing the EMT-dependent red fluorescence protein (RFP) expression in human CRC cells. The RFP expression was quantitatively analyzed to evaluate its association with EMT-related markers and malignant phenotype. Inflammatory cytokines, IL-1β (1 ng/ml) and TNF-α (20 ng/ml), or co-culture with inflammatory mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide (LPS) (200 ng/mL) were used as an inflammatory microenvironment. Biodistribution of EMT cells was analyzed using in vivo experiments with primary and metastatic CRC xenograft tumors.
Results: Inflammatory cytokines reversely induced the RFP expression in association with EMT-related malignant phenotype, such as morphologic change, EMT marker modulation, and invasion ability, in HCT116 and RKO cells. Co-culture with LPS-stimulated inflammatory macrophages also induced the RFP expression by secreting inflammatory cytokines. In vivo experiments revealed that EMT cells were detected within tumor tissues at colon, liver and peritoneum.
Conclusions: Our results suggest that inflammatory microenvironment has a great potential to induce EMT program in CRC cells. This fluorescence-guided EMT imaging system is a useful tool for monitoring the EMT state in the inflammation microenvironment-CRC network in vitro and in vivo.
Citation Format: Hiroshi Tazawa, Takeshi Ieda, Shuya Yano, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara. Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer network in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1101.
Abstract 1104: Tumor-associated macrophages-secreted CXCL1 promotes breast cancer metastasis via activating NF-κB/SOX4 signaling
Authors: Wang Zhiyu , Wang Neng , Liu Weiping , Zheng Yifeng , Wang Shengqi 
Published: August 2018

Abstract
Purpose: Secreted cytokines play a significant role in modulating cancer metastatic microenvironment, especially for tumor associated macrophages (TAMs). The current study aimed to determine the significance of TAMs-secreted CXCL1 in regulating cancer metastasis and its underlying mechanisms. Experimental Design: Cytokine array was utilized to screen the highest chemokine secreted from TAMs. In vivo immunohistochemistry assay and in vitro wound healing or transwell experiments were carried out to demonstrate the metastatic-promoting effects of TAMs/CXCL1. QPCR profile screening was used to identify CXCL1 targeting metastasis-related gene. In vivo luciferase imaging experiments were designed to confirm the therapeutic significance of CXCL1 silencing on breast cancer metastasis. The clinical significance of CXCL1 was analyzed by human tissue microarray and bioinformatic analysis. Results: CXCL1 was validated as the highest secreted protein released from TAMs, and TAMs-derived CXCL1 could promote breast cancer migration and invasion ability, as well as epithelial-mesenchymal transition (EMT) process. QPCR screening validated SOX4 as the most responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 activates SOX4 transcription via NF-κB pathway. CXCL1 silencing in TAMs resulted in a significant reduction in breast cancer growth and metastatic burden. Clinical investigation suggests that high CXCL1 expression was significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Conclusions: TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/sox4 activation, and CAV1 based therapy might become a novel strategy for breast cancer metastasis prevention.
Citation Format: Zhiyu Wang, Neng Wang, Weiping Liu, Yifeng Zheng, Shengqi Wang. Tumor-associated macrophages-secreted CXCL1 promotes breast cancer metastasis via activating NF-κB/SOX4 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1104.
Abstract 1108: M2-polarized macrophages increase invasiveness of EBV-associated nasopharyngeal carcinoma by inducing invadopodia formation
Authors: Tang Wilson Wing Chung , You Chan Ping , Jones Gareth E. , Tsao George Sai-Wah , Tsang Anna Chi Man 
Published: August 2018

Abstract
Cancer metastasis is a major cause of mortality, accounting for approximately 90% of cancer related deaths. Emerging evidences suggest that tumour microenvironment plays an indispensable role in cancer metastasis. Recruitment of innate and adaptive immune cells to the tumour results in chronic inflammation which favours tumour growth and progression. Particularly, tumour associated macrophages (TAMs) are found to promote the initiation, growth, and metastasis in several types of cancers. Nasopharyngeal carcinoma (NPC) is one of the highly invasive and metastatic cancers and is closely associated with EBV infection. We postulate that TAMs may increase the invasiveness of NPC by enhancing the formation of invadopodia, which are membranous actin-rich protrusions with digestive ability of extra-cellular matrix. In this study, monocyte THP-1 cells were polarized to M2-macrophages, and co-cultured with nasopharyngeal cells in a contained chamber-insert. The stimulated nasopharyngeal cells then formed massive numbers of invadopodia and digested larger area of gelatin compared with the unstimulated counterparts. A cytokine antibody array was used to identify the upregulated cytokines in the co-culture medium of the M2-macrohphages and the NPC cells. Tumour necrosis factor alpha (TNFα) was revealed to be the responsible cytokine to induce the formation of invadopodia and digestion of gelatin. Besides, western blot analysis identified that several actin-associated proteins such as Src, Erk, and cortactin were involved in the TNFα-mediated invadopodia formation. We also found that the expression of latent membrane protein 1 (LMP1), an EBV protein that has similar structure to TNF receptor was elevated in NPC cells after co-culturing with the M2-polarized macrophages. Through transient transfection and stable expression of LMP1 in the NPC cells, LMP1 could also promote the formation of invadopodia through cdc42 activation. Taken together, these data indicate macrophages can promote the invasiveness of EBV-infected NPC cells by enhancing their ability in forming invadopodia through an activated TNFα signaling axis and LMP1 upregulation.
Citation Format: Wilson Wing Chung Tang, Chan Ping You, Gareth E. Jones, George Sai-Wah Tsao, Anna Chi Man Tsang. M2-polarized macrophages increase invasiveness of EBV-associated nasopharyngeal carcinoma by inducing invadopodia formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1108.
Abstract 111: The CX3CR1-Fractalkine axis drives both circulating prostate cancer cells and macrophages to the bone metastatic microenvironment
Authors: Kaur Ramanpreet , Qian Chen , Salvino Joseph , Meucci Olimpia , Fatatis Alessandro 
Published: August 2018

Abstract
Prostate cancer (PCa) is the second most frequently diagnosed cancer and its progression into metastatic disease reduces the 5-year survival rate to 29% in diagnosed men. A better understanding of the mechanisms underpinning metastatic dissemination and the role played by the tumor microenvironment at distant sites is essential. Our lab has shown that PCa cells express the chemokine receptor CX3CR1 and seed the skeleton when attracted by bone-derived Fractalkine (FKN) (a.k.a. CX3CL1). A crucial component of the bone microenvironment consists of heterogeneous populations of tumor-associated macrophages (TAMs), which can polarize into M1 or M2 phenotypes and are likely implicated in metastatic progression. TAMs migrate in close proximity of cancer cells and release growth factors, chemokines, and other inflammatory mediators that influence tumor growth. Using cell biology tools, we show that both PCa cells and macrophages express the CX3CR1 receptor, which signal to downstream targets when engaged by FKN and is inhibited by a novel small-molecule inhibitor. We also employed a mouse model of cancer cell dissemination and metastasis to show that our novel CX3CR1 antagonist impairs tumor seeding to the skeleton. Furthermore, as macrophages also express CX3CR1, targeting this receptor may potentially hinder TAMs' accumulation into the metastatic microenvironment, depriving it of crucial pro-metastatic conditioning. In conclusion, we propose that the CX3CR1-FKN axis drives both cancer cells and TAMs to metastatic sites and that the mitigation of the functional interactions between this receptor and its unique chemokine ligand by antagonists of CX3CR1 will impair the clinical progression of PCa metastasis.
Citation Format: Ramanpreet Kaur, Chen Qian, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis. The CX3CR1-Fractalkine axis drives both circulating prostate cancer cells and macrophages to the bone metastatic microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 111.
Abstract 1112: AKT2 loss impairs BRAF mutant melanoma metastasis
Authors: McRee Siobhan K. , Pietruska Jodie R. , Tsichlis Philip N. , Hinds Phil W. 
Published: August 2018

Abstract
Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer, due to its highly metastatic nature. Many melanomas with oncogenic BRAFV600E lose the tumor suppressor PTEN, leading to unconstrained PI3K/AKT signaling and a drastic increase in melanoma invasiveness, but the contribution of AKT to melanoma metastasis has not been fully explored. Differential roles for AKT1 and AKT3 have been suggested in many cancers, but a requirement for AKT2 has not been described in melanoma. We report here that shRNA-mediated, conditional knockdown of AKTs in a variety of human melanoma cell lines reveals that selective AKT2 depletion inhibits migratory and invasive phenotypes in vitro, and prevents metastasis in vivo. Our results support a critical role for AKT2 in stimulating melanoma cell migration and invasion and in supporting growth of metastatic lesions. As AKT inhibitors advance in clinical trials for melanoma, our findings could inform therapeutic strategies to improve treatment options and outcome for this devastating disease.
Citation Format: Siobhan K. McRee, Jodie R. Pietruska, Philip N. Tsichlis, Phil W. Hinds. AKT2 loss impairs BRAF mutant melanoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1112.
Abstract 1113: PODXL1 as a critical accelerator for pancreatic cancer metastasis
Authors: Kondo Eisaku , Saito Ken 
Published: August 2018

Abstract
Podocalyxin-like 1 (PODXL1) is an anti-adhesive transmembrane protein belonging to the CD34 family and also stem cell marker that has been associated with an aggressive tumor phenotype and poor prognosis in several forms of cancer. In this study, we report the biological role of PODXL1 in progression of pancreatic invasive ductal adenocarcinoma (PDAC), especially focusing to invasion and metastasis of PDAC cells. Knockout of PODXL1 gene in three different human PDAC lines, MiaPaCa-2, AsPC1 and Panc-1, almost completely abrogated metastatic lesion in liver-metastatic mouse model in vivo. Molecular analysis revealed that PODXL1 functioned as a critical activator to multiple cytokine receptors expressed on cancer cells, and its interaction facilitated PDAC cell invasion. Endogenous expression of PODXL1 was strongly detected on cancer cells at the invasive front of the PDAC tissues, where coincidently expressed specific cytokine receptor that critically mediates cancer metastasis in vivo. Thus, we identify the novel functional aspect of PODXL1 and its biological role on PDAC as one of the most intractable malignancies.
Citation Format: Eisaku Kondo, Ken Saito. PODXL1 as a critical accelerator for pancreatic cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1113.