bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4496: Myofibroblast-secreted follistatin-like 1 promotes hepatocellular carcinoma formation and metastasis
Authors: Li Natalie Tsz Wai , Tong Man , Zhou Lei , Ning Wen , Lo Chung-Mau , Man Kwan , Lee Terence Kin-Wah , Ma Stephanie Kwai-Yee 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) develops in the setting of fibrosis/cirrhosis, a progressive process in which chronic inflammation and hepatocellular regeneration result in the malignant transformation of hepatocytes. Enrichment of stromal myofibroblasts in this pathological stage is commonly observed, which constitutes the bulk of the tumor microenvironment and contributes to disease progression. Cancer cells are regulated by signals generated intrinsically and extrinsically from the tumor microenvironment. Targeting critical factors involved in this process may offer important therapeutic opportunities. Follistatin-like 1 (FSTL1) has been widely reported as a pro-inflammatory mediator in different fibrosis-related and inflammatory diseases. Here, we report that FSTL1 is either absent or expressed at very low levels in HCC cells, but preferentially secreted from the myofibroblasts of peri-tumor liver and HCC tissue as well as in the liver following acute injury. FSTL1 was found to co-localize and positively correlate with α-SMA, marker of myofibroblasts, in both human HCC as well as in a DEN+CCl4-induced HCC mouse model. High FSTL1 expression in myofibroblast FAP+ cells (FAP+/FSTL1high) also correlated with advanced TNM stages as compared to HCC patients in the FAP+/FSTL1low subgroup. Functional investigations revealed that FSTL1 can induce HCC cell proliferation, metastasis and sorafenib resistance; while FSTL1 attenuation by neutralizing antibody elicited the opposite effects. These observations were further validated in HCC patient-derived organoid cultures in which FSTL1 can enhance the metastatic effect of the cells. Transcriptome sequencing analysis is now currently underway to delineate the underlying molecular mechanism by which myofibroblast-secreted FSTL1 drives carcinogenesis and tumor progression in HCC.
Citation Format: Natalie Tsz Wai Li, Man Tong, Lei Zhou, Wen Ning, Chung-Mau Lo, Kwan Man, Terence Kin-Wah Lee, Stephanie Kwai-Yee Ma. Myofibroblast-secreted follistatin-like 1 promotes hepatocellular carcinoma formation and 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 4496.
Abstract 4502: Cxcl-12-cxcr4 inhibition enhances immune response in pancreatic ductal adenocarcinoma
Authors: Garg Bharti , Ferrantella Anthony , Giri Bhuwan , Modi Shrey , Sethi Vrisketan , Kurtom Saba , Banerjee Sulagna , Sundaram Ramakrishnan , Gilboa Eli , Saluja Ashok , Dudeja Vikas 
Published: August 2018

Abstract
Introduction: Pancreatic ductal adenocarcinoma, one of the most aggressive malignancies and is refractory to Immunotherapy. This, in part, is mediated by the fibrotic stroma, creating an immune-suppressive microenvironment. CXCL12/SDF-1 has been shown to act as a chemo-repellant in several cancers. Therefore, we evaluated the role of stromal CXCL-12 in mediating an immunosuppressive phenotype within the pancreatic tumor.
Methods: Pancreatic cancer cells harvested from KPC, a genetically engineered mouse model for PDAC, were either injected or alone or co-injected with pancreatic stellate cells (PSCs) extracted from WT (C57/BL6) mice to induce tumors. SDF-1 expression levels were detected by IF and q-RT PCR in tumor sections. An SDF-1 inhibitor, AMD3100 (2mg/kg), or vehicle was administered i.p for 21 days in tumor bearing mice and tumor growth and immune infiltration were assessed as an end point by flow cytometry. To evaluate the T cell migration in vitro, PSCs were pre-treated with SDF-1 neutralizing antibody, educated with KPC cancer cells and further co-cultured with splenic CD3+ T cells extracted from KPC mice.
Results: In vitro results showed markedly increased secretion of SDF-1 by PSCs and neutralization of SDF-1 led to increased T-cell migration when cultured with cancer cells alone. We also evaluated the effect of inhibition of SDF-CXCR4 axis on tumor growth. Co-injection of KPC with WT PSC formed larger tumors with increased section of CXCL-12 as compared to when KPC cells were injected alone. Interestingly, Inhibition of SDF-1-CXCR4 interaction with AMD3100 led to reduced tumor growth with increased infiltration of activated CD8+ cytotoxic T cells as compared to the saline-treated mice.
Conclusion: Our results indicate that stromal cells contribute to tumor progression by blocking the infiltration of cytotoxic T cells via secretion of CXCL-12. Targeting CXCL-12 could pave the way for designing better therapeutic interventions against pancreatic cancer.
Citation Format: Bharti Garg, Anthony Ferrantella, Bhuwan Giri, Shrey Modi, Vrisketan Sethi, Saba Kurtom, Sulagna Banerjee, Ramakrishnan Sundaram, Eli Gilboa, Ashok Saluja, Vikas Dudeja. Cxcl-12-cxcr4 inhibition enhances immune response in pancreatic ductal adenocarcinoma [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 4502.
Abstract 4506: Loss of SIRT1 alters the secretome of breast cancer cells by impairing lysosomal integrity
Authors: Latifkar Arash , Ling Lu , Zhang Xiaoyu , Fischbach Claudia , Lin Hening , Cerione Richard , Antonyak Marc 
Published: August 2018

Abstract
Sirtuin 1 (SIRT1) is an NAD-dependent deacetylase implicated in processes ranging from lifespan promotion to tumor suppression. To probe its role as a tumor suppressor, we knocked down SIRT1 in breast cancer cells. This resulted in the decreased expression of one of the subunits comprising the multi-subunit vacuolar-type H+ ATPase (V-ATPase), which is responsible for the acidification of lysosomes and thus essential for proper lysosomal protein degradation. The impairment in lysosomal function led to a marked reduction in the number of multivesicular bodies (MVBs) targeted for lysosomal degradation, and a corresponding increase in MVBs fusing with the plasma membrane to release their content. Specifically, SIRT1 reduction increased the secretion of exosomes containing unique cargo and the release of soluble hydrolases that typically reside in the lysosome, producing a breast cancer cell secretome that strongly promotes cell invasion and survival.
Citation Format: Arash Latifkar, Lu Ling, Xiaoyu Zhang, Claudia Fischbach, Hening Lin, Richard Cerione, Marc Antonyak. Loss of SIRT1 alters the secretome of breast cancer cells by impairing lysosomal integrity [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 4506.
Abstract 4509: SATB2/β-catenin/TCF-LEF pathway induces cellular transformation by generating cancer stem cells in colorectal cancer
Authors: Ma Yiming , Yu Wei , Shankar Sharmila , Srivastava Rakesh K. 
Published: August 2018

Abstract
Recent studies have demonstrated the involvement of colorectal cancer (CRC) stem cells (CSC) in transformation, cancer progression and metastasis. The main goal of this paper was to examine the molecular mechanisms by which SATB2 induced malignant transformation of colorectal epithelial cells. SATB2 induced malignant transformation and these transformed cells gained the characteristics of CSCs by expressing stem cell markers (CD44, CD133, LGR5 and DCLK1) and transcription factors (c-Myc, Nanog and Sox2). Overexpression of SATB2 in normal colorectal epithelial cells increased cell motility, migration and invasion, which were associated with an increase in N-cadherin and Zeb1, and decrease in E-cadherin expression. SATB2 overexpression also upregulated XIAP and cyclin D1, suggesting its role in cell survival and cell cycle. Furthermore, the expression of SATB2 was positively correlated with β-catenin expression in CRC. In contrary, depletion of SATB2 inhibited cell proliferation, colony formation, cell motility and expression of β-catenin, Snail, Slug, Zeb1 and N-cadherin, and upregulated E-cadherin. Furthermore, SATB2 silencing inhibited the expression of stem cell markers, pluripotency maintaining transcription factors, cell cycle and cell proliferation/survival genes and TCF/LEF targets. Finally, β-catenin/TCF-LEF pathway mediated the biological effects of SATB2 in CSCs. These studies support the role of SATB2/β-catenin/TCF-LEF pathway in transformation and carcinogenesis.
Citation Format: Yiming Ma, Wei Yu, Sharmila Shankar, Rakesh K. Srivastava. SATB2/β-catenin/TCF-LEF pathway induces cellular transformation by generating cancer stem cells in colorectal 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 4509.
Abstract 4514: ASR458, a small molecule, targets Notch1 signaling in advanced colorectal cancer
Authors: Chandrasekaran Balaji , Pal Deeksha , Tyagi Ashish , Ramisetti Srinivasa R , Sharma Arun K , Ankem Murali , Damodaran chendil 
Published: August 2018

Abstract
Cancer-related mortality rates are amongst the highest in colorectal cancer (CRC). Previously we have reported that Withaferin A (WA), a natural compound, induces apoptosis and inhibits AKT mediated pro-survival signaling resulting in growth inhibition both in vitro and in vivo models of colon cancer. Owing to the encouraging results with WA, we have developed a series of acetylated pro-drug conjugates of WA and our initial structure-activity relationship (SAR) studies led to the identification of a novel small molecule ASR-458 as the lead compound. Interestingly, ASR-458 has demonstrated better efficacy by inhibiting colon cancer cell growth at nano-molar concentration, even in AKT overexpressing (AKT/HCT) HCT-116 cells (IC50: 750nm). Induction of apoptosis was seen in both control vector and AKT overexpressed colon cancer cell lines. Induction of caspase mediated signaling confirmed the pro-apoptotic function of ASR-458 in colon cancer cells. Inhibition of pAKT (ser473) resulted in downregulation of Notch1 downstream signaling pathways (Presenilin 1, NFkB activation and BCl-2 expression) in AKT/HCT colon cancer cells. Epithelial to mesenchymal transition (EMT) is a major hallmark of metastatic colon cancer. ASR-458 also downregulated the expression of EMT markers snail as well as β-Catenin and significantly impaired invasive as well as the migratory efficiency of AKT/HCT cells. Our ongoing xenograft studies will validate the in vivo efficacy of ASR-458 (1mg/kg/BW by IP weekly 2 times for six weeks) will confirm the chemotherapeutic effect of the compound against colon cancer cells. Overall these results emphasize ASR-458 to be a promising small molecule as compared to WA. ASR-458 targets both AKT and Notch1 signaling pathways which remains an important target for the development of effective treatment of metastatic stage of CRC.
Citation Format: Balaji Chandrasekaran, Deeksha Pal, Ashish Tyagi, Srinivasa R Ramisetti, Arun K Sharma, Murali Ankem, chendil Damodaran. ASR458, a small molecule, targets Notch1 signaling in advanced colorectal 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 4514.
Abstract 4520: Using SEREX approach to screen and identify the tumor-associated antigens in non-small cell lung cancer
Authors: Pei Lu , Wang Tingting , Wang Peng , Liu Hongchun , Ouyang Songyun , Zhang Jianying , Dai Liping 
Published: August 2018

Abstract
Background: Lung cancer is the most common cause of cancer-related deaths worldwide and approximately 85% of lung cancer cases are non-small-cell lung cancer (NSCLC). The average survival and 5-year survival rates of NSCLC patients still remain poor. Autoantibodies against tumor-associated antigens (TAAs) have been shown to be relevant tumor markers. There is an urgent need to better understand the mechanism and to identify useful biomarkers for early immunodiagnosis of NSCLC.
Materials and methods: Serological analysis of recombinant tumor cDNA expression libraries (SEREX) was applied to screen the lung cancer tumor-associated antigens (TAAs) with sera from lung cancer patients. Oncomine online database was used to analyze multiple microarray datasets and to identify potential genes in NSCLC progression. Autoantibody responses to TAAs were evaluated by enzyme-linked immunosorbent assay (ELISA) in sera from 196 patients with NSCLC and 196 normal controls.
Result: Seventy positive clones had been screened by SEREX approach and 35 genes with known biological function were further identified by mass spectrometry analysis. Ten out of 35 genes were determined to be tested the corresponding autoantibodies since they were consistently over-expressed in NSCLC tissue in three mRNA arrays. The results of ELISA show that the level and positive frequency of the autoantibodies to TOP2A,ACTR3, RPS6KA5 and PSIP1 in sera from NSCLC patients were significantly higher than that in normal control (Ρ&lt;0.05). The sensitivity of the four autoantibodies for diagnosis of NSCLC ranged from 17.4% to 32.1% with the specificity of 90%. The area under curve(AUC)of TOP2A,ACTR3, RPS6KA5 and PSIP1 was 0.758, 0.787, 0.707 and 0.668, respectively. The sensitivity of the panel of this four TAAs was 47.2% and the specificity was 81.5%.
Conclusions: TOP2A, ACTR3, PSIP1, RPS6KA5 were tumor-associated antigens and their autoantibodies might be potential biomarkers for immunodiagnosis of NSCLC.
Citation Format: Lu Pei, Tingting Wang, Peng Wang, Hongchun Liu, Songyun Ouyang, Jianying Zhang, Liping Dai. Using SEREX approach to screen and identify the tumor-associated antigens in non-small cell lung 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 4520.
Abstract 453: The role of centrosome amplification in HCC
Authors: Yeung Sai Fung , Ching Yick Pang 
Published: August 2018

Abstract
Centrosome is the major microtubule organizing center (MTOC) in mammalian cells which maintain cell polarity, organization of microtubules and regulate cell cycle progression. In normal cells, centrosome duplication cycle is tightly coupled with cell cycle, DNA synthesis, mitosis as these event were controlled by parallel pathways. Centrosomal defect is reported in numerous type of solid and hematologic malignancy, both structurally (enlarged PCM, string-like etc) and numerically (&lt;2 or &gt;=3). Centrosome amplification (CA, n&gt;=3) is the most commonly reported. CA is casually linked to chromosomal instability (CIN), tumor-initiation, advanced tumor stage and chemo-resistance. CA arises through multiple distinct but non-redundant mechanisms in tumor, for example, aberrant cell cycle, hypoxia, and chemotherapy. Recently studies suggest CA might not be responsible for HCC initiation. Yet, around 90% of HCC cells carry certain degree of CA. It is associated with p53 mutation and tumor-aneuploidy but no other clinicopathological features. The role of CA in HCC progression deserve a more comprehensive study. To investigate the role of CA in HCC, first, we use CA20, an expression signature-score includes centrosomal structural genes and genes results in CA when dyregulated. We use CA20 as surrogate marker to evaluate the clinical outcome of CA in HCC from GEO datasets. CA carrying HCC was found to have poor overall survival and larger tumor size. Next, we developed several inducible PLK4 overexpressing HCC cell line. Preliminary data shown that PLK4 overexpression concomitantly leaded to centrosome over-duplication in HCC cell lines. Functionally, PLK4 overexpression resulted in increased cell migration, but retarded growth rate in p53+/+ HCC cells. Furthermore, we identified another cell cycle-related kinase - Aurora A, as a novel interacting partner of PLK4 suggest that these kinases work together to promote malignant transformation.
Citation Format: Sai Fung Yeung, Yick Pang Ching. The role of centrosome amplification in HCC [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 453.
Abstract 4577: ESR1 methylation: A liquid biopsy-based epigenetic assay for the follow up of patients with metastatic breast cancer receiving endocrine treatment
Authors: Mastoraki Sofia , Strati Areti , Tzanikou Eleni , Chimonidou Maria , Politaki Eleni , Voutsina Alexandra , Psyrri Amanda , Georgoulias Vassilis , Lianidou Evi S. 
Published: August 2018

Abstract
Introduction: Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of CTCs and plasma-ctDNA. ESR1 epigenetic silencing potentially affects response to endocrine treatment. We evaluated ESR1 methylation in CTCs and paired plasma-ctDNA. We evaluated ESR1 methylation in CTCs and paired plasma-ctDNA as a potential biomarker for response to everolimus/exemestane treatment. Materials and methods: A highly sensitive and specific real-time MSP assay for ESR1 methylation was developed and validated in: a) 65 primary breast tumors (FFPEs), b) EpCAM+ CTC-fractions (122 patients and 30 healthy donors; HD), c) plasma-ctDNA (108 patients and 30HD), d) in CTCs (CellSearch®) and in paired plasma-ctDNA for 58 BrCa patients. ESR1 methylation status was investigated in CTCs isolated from serial peripheral blood samples of 19 patients with ER+/ HER2- advanced BrCa receiving everolimus/exemestane. Results: ESR1 methylation was detected in: a) 25/65(38.5%) FFPEs, b) EpCAM+ CTC-fractions: 26/112(23.3%) patients and 1/30(3.3%) HD, c) plasma-ctDNA: 8/108(7.4%) patients and 1/30(3.3%) HD. ESR1 methylation was highly concordant in 58 paired DNA samples, isolated from CTCs (CellSearch®) and corresponding plasma. In serial peripheral blood samples of patients treated with everolimus/exemestane, ESR1 methylation was observed in 10/36(27.8%) CTC-positive samples, and was associated with lack of response to treatment (p=0.023 Fisher's Exact Test). Conclusions: We report for the first time the detection of ESR1 methylation in CTCs and a high concordance with paired plasma-ctDNA. ESR1 methylation in CTCs was associated with lack of response to everolimus/exemestane regimen. ESR1 methylation should be further evaluated as a potential liquid biopsy-based biomarker.
Citation Format: Sofia Mastoraki, Areti Strati, Eleni Tzanikou, Maria Chimonidou, Eleni Politaki, Alexandra Voutsina, Amanda Psyrri, Vassilis Georgoulias, Evi S. Lianidou. ESR1 methylation: A liquid biopsy-based epigenetic assay for the follow up of patients with metastatic breast cancer receiving endocrine treatment [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 4577.
Abstract 4602: PTEN and ERG expression in MRI-ultrasound guided fusion biopsy correlated with radical prostatectomy findings in men with prostate cancer
Authors: Erickson Andrew , Lokman Utku , Lahdensuo Kanerva , Tornberg Sara , Visapää Harri , Bergroth Robin , Santti Henrikki , Petas Anssi , Mirtti Tuomas , Rannikko Antti 
Published: August 2018

Abstract
Introduction & Objectives
We previously compared ERG and PTEN protein expression in systematic biopsies with radical prostatectomy (RP) findings. MRI-Ultrasound (MRI-US) guided biopsies are expected to more accurately reflect the biological changes in the RP specimens. Here, we studied the correlation of PTEN and ERG status in MRI-US fusion biopsies (FBx) and RP specimens, and assessed the predictive value of FBx on disease stage and grade at RP.
Material & Methods
The study included patients who had undergone RP in Helsinki University Hospital between June 2015 and May 2017, and had preoperative FBx tissue available (n=110). Matched FBx specimens and tissue microarrays constructed from RP were immunostained with ERG and PTEN antibodies, and scored as either negative or positive. The RP TMA contained one to three clinically relevant cancer foci per patient.
Results
A high correlation of both PTEN and ERG status was observed between FBx and RP materials (Table 1). The correlation of PTEN status was particularly better compared with our previous findings in systematic 12-core biopsies (Lokman et al. 2017), where there was no significant concordance. High grade RP (grade group 4&5) correlated with ERG negativity in FBx (p=0.021), whereas PTEN was lost in high stage RP (pT≥3) to a higher extent than in low stage RP (pT2, p= n.s). Higher FBx grade group was associated with stage increase in RP (p=0.014).
Conclusions
FBx is feasible method to assess ERG and PTEN status correctly in RP specimens. More validation studies, accompanied with MRI features, are warranted.
Table 1A. Concordance of ERG IHC status in fusion biopsies (FBx) and radical prostatectomy (RP) specimens.RP ERG NegativeRP ERG PositiveP-valueFBx ERG Negative54 (90.0)6 (10.0)&lt;0.001aFBx ERG Positive3 (7.1)39 (92.9)Table 1B. Concordance of PTEN IHC (Any PTEN Loss) status in FBx and RP specimens.RP Any PTEN LossRP PTEN IntactP-valueFBx Any PTEN Loss14 (73.7)5 (26.3)0.002aFBx PTEN Intact22 (32.4)46 (67.6)Table 1C. Concordance of PTEN IHC (Complete PTEN Loss) status in FBx and RP specimens.RP Complete PTEN LossRP PTEN IntactP-valueFBx Complete PTEN Loss6 (50.0)3 (50.0)&lt;0.001aFBx PTEN Intact3 (4.0)72 (96.0)aFisher''s exact test. All p-values two-tailed.
Citation Format: Andrew Erickson, Utku Lokman, Kanerva Lahdensuo, Sara Tornberg, Harri Visapää, Robin Bergroth, Henrikki Santti, Anssi Petas, Tuomas Mirtti, Antti Rannikko. PTEN and ERG expression in MRI-ultrasound guided fusion biopsy correlated with radical prostatectomy findings in men with 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 4602.