bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4051: Different immune signatures in advanced lung tumors of Nrf2 wildtype vs. knockout mice
Authors: Zhang Di , Rennhack Jonathan , Andrechek Eran , Rockwell Cheryl , Liby Karen 
Published: August 2018

Abstract
Activation of Nrf2 and its downstream target genes serves as a master defense mechanism, protecting cells against oxidative and electrophilic stress. Numerous activators of Nrf2 inhibit carcinogenesis. However, genetic alterations resulting in constitutive Nrf2 activation in human lung tumors promotes tumor growth and chemoresistance. The dual role of Nrf2 in cancer has generated a high level of interest, but little is known regarding the effect of Nrf2 on immune cells during lung carcinogenesis. In this study, we used the potent carcinogen vinyl carbamate to induce lung tumors in mice. Tumor burden, the immunophenotype, and genetic signatures were compared in the lungs of Nrf2 knockout (-/-, KO) vs. wildtype (+/+, WT) mice. Nrf2 KO mice were more susceptible to vinyl carbamate; these mice developed tumors earlier than the WT mice and exhibited more and larger tumors over times ranging from 20-32 weeks after initiation. By 32 weeks, WT mice have an average of 6.5 ± 0.95 tumors per lung compared to 12.25 ± 2.6 tumors in the KO mice. Immune cell populations including T cells (CD4+ and CD8+), B cells, macrophages and myeloid derived suppressor cells were investigated in the lungs and spleens of Nrf2 WT and KO mice challenged with vinyl carbamate. T cell populations were significantly (P &lt; 0.05) reduced in the lungs of Nrf2 KO mice, while tumor-promoting macrophages and myeloid derived suppressor cells were elevated in the lung and spleen, respectively, of Nrf2 KO mice compared to WT mice. Moreover, immune response genes, especially a series of cytokines (Cxcl1, Cxcl12, Csf1, and Ccl9) and MHC antigens that promote tumor growth, were significantly upregulated in tumors from Nrf2-/- mice. Importantly, this expression profile is conserved in patients with lung cancer. Overall, our results confirmed a tumor protective role of Nrf2 in carcinogenesis and suggest an important regulatory role for Nrf2 in immune cells in both mouse and human lung tumors.
Citation Format: Di Zhang, Jonathan Rennhack, Eran Andrechek, Cheryl Rockwell, Karen Liby. Different immune signatures in advanced lung tumors of Nrf2 wildtype vs. knockout mice [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 4051.
Abstract 4115: Comparison of IL-4 receptor targeting elastin-like polypeptide based on size and structure
Authors: Seo Boyeon , Sarangthem Vijaya , Yi Aena , Park Rang-Woon 
Published: August 2018

Abstract
For novel drug delivery systems, in order to improve clinical outcomes clear optimization of size, shape, multifuntionality, and site-specificity are highly considered. As molecular size significantly influenced the biodistribution, precise control of molecular sizes must be considered for optimum targeting effect in cancer therapy. Elastin like polypeptide (ELP), has been utilized as an attractive vehicle for cancer therapy as it provide unparalleled control over sequence and structure in genetic level thereby allowing generation of various polymers with defined architectures and functional properties. In this study, we designed various multivalent elastin-like polypeptide based tumor targeting polymer in which multiple copies of IL-4 receptor (IL-4R) targeting ligands, AP1 peptide were subjected into ELP polymer backbone periodically to enhance affinity and avidity towards IL-4R- highly expressed tumor cells. Several ELP with different molecular sizes and structure from unimer to micelle forming polymer have been designed to investigate the pattern of accumulation in tumor, as well as their bio-distribution in vivo. Different percentage of cell binding and uptake depend on size, number of targeting peptides, or based on unimer compared with micelle were determined. The high molecular weight AP1-ELP showed superior binding activity with faster entry and efficiently processed in the IL-4R dependent endocytic pathway compared to low molecular weight polypeptides. In addition the high molecular weight, micelle forming AP1-ELP displayed better tumor penetration and extensive retention in tumor tissue with decrease non-specific accumulation in vital organs compared to low molecular weight AP1-ELP in xenograft model. It was suggested that superior binding activities shown by A86 and A100 may depends on multiple presentation of ligands upon transition to micelle like structure rather than increased number of targeting ligands and molecular weight. Thus this study have significance in demonstrating different pattern underlying unimer and micelle forming ELP mediated tumor targeting as well as biodistribution in vivo.
Citation Format: Boyeon Seo, Vijaya Sarangthem, Aena Yi, Rang-Woon Park. Comparison of IL-4 receptor targeting elastin-like polypeptide based on size and structure [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 4115.
Abstract 4126: DNA methyltransferase inhibitors target a YES1-YAP1 signaling axis in childhood rhabdomyosarcoma
Authors: Slemmons Katherine , Yeung Choh , Baumgart Josh , McCalla-Martin Amy , Helman Lee 
Published: August 2018

Abstract
We have previously shown that the SRC family kinase (SFK) member, YES1, is highly expressed and rapidly activated upon IGF-1R blockade in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and adolescents. YAP1 (YES-associated protein) is also highly expressed in human RMS tumors where it functions as an oncoprotein when the upstream Hippo tumor suppressor pathway is silenced, driving cell growth and survival. Thus far, efforts to pharmacologically inhibit YAP1 have been unsuccessful. One activator of the Hippo pathway, RASSF1a, is epigenetically silenced in many cancer types including sarcomas. Here we show a loss of RASSF1a expression in RMS cell lines via promoter methylation. Treatment with DNA methyltransferase inhibitors (DNMTis) can re-activate RASSF1a expression, resulting in YAP phosphorylation and inactivation. DNMTi treatment also significantly inhibits RMS cell growth, which can be rescued by overexpression of a constitutively active YAPS127A. In the alveolar variant (aRMS) in particular, DNMTis increase apoptosis and decrease both YES1 expression and activation. This suggests DNMTi treatment can inhibit both YAP1 and YES1 signaling. To further investigate the connection between YES1 and YAP1 we performed proximity ligation assays and discovered that YES1 and YAP1 interact in the nucleus of RMS cell lines. Furthermore, dasatinib treatment, a known SFK inhibitor, prevents YAP1 nuclear accumulation suggesting a role for YES1 in regulating YAP1 cellular localization. YAP1 is also tyrosine phosphorylated, which may be one way YES1 regulates YAP1. Lastly, cells expressing a constitutively active YAPS127A have increased activation of SFK suggesting a positive feedback loop whereby YAP1 activity can further activate YES1 through an unknown mechanism. These data uncover a signaling axis between the YES1 and YAP1 oncoproteins in RMS and suggest an alternative way to silence YES1 and YAP1 through use of DNMTis. We will further analyze this signaling through shRNA knockdown of YES1 and evaluate combination treatment of a DNMTi and dasatinib in vitro and in vivo.
Citation Format: Katherine Slemmons, Choh Yeung, Josh Baumgart, Amy McCalla-Martin, Lee Helman. DNA methyltransferase inhibitors target a YES1-YAP1 signaling axis in childhood rhabdomyosarcoma [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 4126.
Abstract 4151: Fucoidan reduced radiation-induced fibrosis and secondary primary cancers
Authors: Wu Szu-yuan 
Published: August 2018

Abstract
Radiotherapy (RT) causes tissue fibrosis and secondary cancers. Fucoidan is a sulfated polysaccharide that is mainly found in brown algae and brown seaweed. In this study, we assessed the radioprotective effect of oligo-fucoidan on zebrafish. Embryos were exposed to RT (5, 10, or 20 Gy) at 4 hours post-fertilization and compared with an oligo-fucoidan pretreatment group. We found that oligo-fucoidan protects embryos from death and embryonic defects. Using oligo-fucoidan oral feeding adult zebrafish prior radiation, we found that oligo-fucoidan treatment of wild-type fish yields much lower expression of apoptosis and fibrosis marker genes in liver compared to RT (40 Gy) only. Liver fibrosis was diagnosed from Sirius stain, proved oligo-fucoidan reduce fibrosis caused by high dose of radiation. Using a diet-induced obesity HBx,src(p53-) triple transgenic fish liver cancer model, we found that oligo-fucoidan can lower the expression of cell cycle/proliferation markers, as well as fibrosis markers and lipogenic enzymes, compared with that in fish with radiation exposure only. Furthermore, oligo-fucoidan can effectively decrease liver cancer formation, as observed by hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) staining of PCNA proliferation marker. Genomic transcriptome profiling by GeneTitan reveals the main genes/pathways activated by oligo-fucoidan pre-treatment which have protection effect for the radiation-induced fibrosis and secondary primary cancers. Our results provide evidence for the ability of oligo-fucoidan to prevent steatosis, hepatocellular carcinoma and secondary cancers induced by radiation in zebrafish model.
Citation Format: Szu-yuan Wu. Fucoidan reduced radiation-induced fibrosis and secondary primary cancers [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 4151.
Abstract 4166: Hair follicles as a minimally invasive resource of epithelial cells in mouse studies of ionizing radiation
Authors: Slavik Hanus , Mistrik Martin , Duskova Pavlina , Furst Tomas , Srovnal Josef , Hajduch Marian 
Published: August 2018

Abstract
Introduction
Hair follicles are relatively accessible as a biological material allowing repeatable and minimally invasive sampling of predominantly epithelial cells for biomarker studies. The utility of such a material is promising for example in murine experiments, where repeated sampling would require multiple biopsies. As a proof of concept, the ionizing irradiation response in murine follicular cells was chosen as a suitable and common external factor for studying cellular senescence, apoptotic pathways, neoplastic transformation, tumor development and response to cancer therapy.
Methods and material
Hair follicles were collected from 30 healthy C57Bl/6 mice into the RNA later for RT-qPCR and into the 4% formaldehyde for immunofluorescence with specially developed vacuum collector. Follicles were collected before X-ray irradiation and 30 min, 3 h, 6 h and 24 h after irradiation. Each group of 10 mice obtained one dose (2, 6 or 10 Gy). RNA was extracted from the samples using miRNeasy mini kit (Qiagen) and two-tube RT-qPCR was performed for SESN1, p21, MDM2 and HPRT gene expression analysis. Immunofluorescence was done for γ-H2AX and quantitatively evaluated by in-house developed software routine.
Results
Total RNA extracted from one pluck was usually less than 35 ng but it had good quality (RIN ≥ 7.5) even after the storage at room temperature. We determined p21 as the best marker for the uniformity and specific dynamic respond for each of the doses. The strongest responds were found after 30 min with 2 Gy (average fold change FCav = 3,24). In case of higher doses, longer remaining p21 overexpression was detected. For instance, FCav = 2,29 even after 24h at dose 10 Gy. Our data were corroborated by immunofluorescence for direct marker of ionizing radiation induced DNA damage γ-H2AX, where 1-3 hair follicles proved to be efficient for microscopic analyses. Strong γ-H2AX signal was detectable within 3h after irradiation followed by rapid decrease within the next 24h.
Conclusion
Collected murine hair follicles proved to be a feasible alternative material for molecular analyses which in logistic aspects outreaches phlebotomies or skin biopsies because of repeatable, minimally invasive and accurate sampling and non-laborious processing.
Dedication
This work was financially supported by grants IGA_LF_2017_013, EATRIS-CZ, TACR TE02000058 and VG20102014001.
Citation Format: Hanus Slavik, Martin Mistrik, Pavlina Duskova, Tomas Furst, Josef Srovnal, Marian Hajduch. Hair follicles as a minimally invasive resource of epithelial cells in mouse studies of ionizing radiation [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 4166.
Abstract 4178: AKT-ERK axis in circulating tumor cells is a target for metastatic suppression
Authors: Cheng Hung-Chi , Wang Ying-Jan , Cheng Li-Hsin 
Published: August 2018

Abstract
Cytotoxic cancer therapies often result in unwanted side effects, drug resistance, and cancer metastasis. To avoid this, an anti-metastatic therapeutic strategy independent of apoptosis is alternatively desired. Malignant circulating tumor cells (CTCs) may escape from anoikis by sustaining AKT survival signals. Moreover, cancerous fibronectin polymers (polyFN) are known to mediate the adhesion of CTCs to endothelia and lung metastasis. Depletion of polyFN from CTCs without lowering AKT signaling may thus be an ideal anti-metastatic approach. Screening several phytochemical compounds, we found that Pterostilbene (PS), a resveratrol derivative, potently reduced polyFN on suspended tumor cells, whereas it significantly elevated AKT phosphorylation (pAKT), apparently in contrast to its well-known anti-apoptotic effect on adherent tumor cells. Inactivation of ERK signaling in suspended tumor cells was responsible for the enhanced pAKT by PS, leading to suppressions of polyFN assembly and tumor metastasis. Pretreatment with a PI3K inhibitor, LY294002, effectively reduced PS-activated AKT, rescued PS-inactivated ERK, and consequently reversed the PS-suppressed polyFN assembly which was then overturned by the ERK inhibitor U0126. Indeed, PS-suppressed lung metastasis was counteracted by LY294002, which was reversed with U0126. Dietary PS may serve as a novel complementary medicine, for it could be orally administered and efficiently blockaded tumor metastasis by targeting AKT-ERK signaling axis in CTCs.
Citation Format: Hung-Chi Cheng, Ying-Jan Wang, Li-Hsin Cheng. AKT-ERK axis in circulating tumor cells is a target for metastatic suppression [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 4178.
Abstract 4194: Tumor Treating Fields (TTFields) affect invasion properties and cell morphology of various cancer cells in vitro
Authors: Schneiderman Rosa S. , Giladi Moshe , Zeevi Einav , Shteingauz Anna , Voloshin Tali , Porat Yaara , Munster Mijal , Kirson Eilon D. , Palti Yoram 
Published: August 2018

Abstract
Tumor Treating Fields (TTFields) therapy is an approved modality for the treatment of glioblastoma. TTFields are delivered via continuous, noninvasive application of low intensity, intermediate frequency alternating electric fields. The antimitotic effects of TTFields have been extensively investigated. We explored other processes that may be affected by TTFields such as cellular invasion. Human glioma, human and mouse melanoma, human breast cancer and human colon cancer cell lines were treated with TTFields using the inovitro system. Invasion assays were performed using a modified Matrigel coated Boyden chamber. TTFields effect on cells size, focal adhesions and stress fibers morphology was studied using immuno-fluorescent confocal microscopy.
Invasion was significantly reduced compared to untreated cells in all tested cell lines.
Furthermore, the optimal frequency for inhibition of invasion in tested cells was 300 kHz while the optimal anti mitotic frequency leading to glioma cell death is 200 kHz. The inhibitory effect on migration was observed at electric fields intensities of 0.6 V/cm RMS which is below the 1 V/cm RMS threshold previously reported for induction of cell death. Combining TTFields with Bumetanide, an agent that inhibits cellular motility, resulted in further inhibition of glioma cell invasion.
TTFields application resulted in an increase in cell size, as well as in focal adhesion size, number and peripheral distribution of the adhesion sites. Also, treated cells adopted a more flattened and spread shape in comparison with control cells.
TTFields treated cells exhibit reduction in appearance of stress fibers and a dense meshwork of actin filaments around the entire cell periphery.
Our results suggest that cancer cell motility is impaired by exposure to TTFields. The TTFields parameters (intensity and frequency) which led to the maximal inhibition of cellular motility are different from those required for exerting anti-mitotic effects. The alterations in cells morphology during exposure to TTFields may contribute to reduction in cell motility. Further studies are needed to elucidate the mechanism by which TTFields disrupts cellular motility in glioma cancer cells.
Citation Format: Rosa S. Schneiderman, Moshe Giladi, Einav Zeevi, Anna Shteingauz, Tali Voloshin, Yaara Porat, Mijal Munster, Eilon D. Kirson, Yoram Palti. Tumor Treating Fields (TTFields) affect invasion properties and cell morphology of various cancer cells in vitro [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 4194.
Abstract 4195: β-elemene inhibits the metastasis of multidrug-resistant gastric cancer cells through the Cbl-b-EGFR-ERK/Akt signaling pathway
Authors: Yu Ruoxi , Deng Mingming , Song Huicong , Zou Dan , Xu Ling , Qu Xiujuan , Liu Yunpeng , Teng Yuee , Hu Xuejun , Zhang Ye 
Published: August 2018

Abstract
Background/Aims: β-elemene, a Curcuma wenyujin plant extract, has been widely used as an adjuvant therapeutic agent in cancer treatment. The emergence of drug-resistant tumor cells is defined as multidrug resistance (MDR), and is one of the major ways cancer therapy can fail. Our previous study indicated that, compared to chemo-sensitive human gastric cancer cells, drug-resistant cells have a stronger ability for migration. The aim of this study was to explore the anti-metastasis effects and mechanism of β-elemene in multi-drug resistance human gastric cancer cells.
Methods: A cell viability assay was used to assess the resistance of adriamycin-resistant human gastric cancer SGC7901 cells (SGC7901/ADR) and the cytotoxic effects of β-elemene on SGC7901/ADR cells. A wound healing assay and transwell assay were used to explore the anti-metastasis effects of β-elemene. Human matrix metalloproteinase (MMP) antibody array and Western blot analysis were used to explore the potential mechanism. A murine tumor metastasis assay was used to confirm the anti-metastasis effects in vivo. Immunohistochemistry analysis was performed to examine the expressions of related proteins in xenograft tumors.
Results: At sub-lethal concentrations (1 μg/ml and 5 μg/ml), β-elemene significantly inhibited cell migration and invasion of SGC7901/ADR cells. The human MMP antibody array indicated that β-elemene could regulate almost all proteins of the MMP family, and changes of MMP-2 and MMP-9 were the most obvious. Western blotting showed an increase of E-cadherin and decrease of vimentin in β-elemene-treated cells. Downregulation of transcription factor ZEB1 and ZEB2 was also detected. Treatment of SGC7901/ADR cells with β-elemene led to downregulation of Akt, ERK, and EGFR phosphorylation, and significant upregulation of the E3 ubiquitin ligase, Cbl-b. Changes of these proteins were confirmed in xenograft tumors. Hematoxylin and eosin staining showed significantly decreased numbers of metastatic tumor colonies in the lungs of nude mice injected with SGC7901/ADR cells and β-elemene compared with those only injected with SGC7901/ADR cells.
Conclusions: The results strongly suggest that β-elemene inhibits the metastasis of multidrug-resistant gastric cancer cells in vitro and in vivo by regulating the Cbl-b-EGFR-ERK/Akt signaling pathway. β-elemene may be a promising treatment for multidrug resistant human gastric cancer.
Citation Format: Ruoxi Yu, Mingming Deng, Huicong Song, Dan Zou, Ling Xu, Xiujuan Qu, Yunpeng Liu, Yuee Teng, Xuejun Hu, Ye Zhang. β-elemene inhibits the metastasis of multidrug-resistant gastric cancer cells through the Cbl-b-EGFR-ERK/Akt signaling pathway [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 4195.
Abstract 4197: Sulforaphane suppresses metastasis via autophagic degradation of cathepsin S in oral cancer cells
Authors: Lin Chiao-Wen , Chen Chang-Tai , Yang Shun-Fa 
Published: August 2018

Abstract
Sulforaphane has been demonstrated to exert numerous biological effects, such as neuroprotective, anti-inflammatory, and anticancer effects. However, the detailed effects of sulforaphane on human oral cancer cell metastasis and the underlying mechanisms remain unclear. In this study, we observed that sulforaphane attenuated SCC-9 and SCC-14 cell motility and invasiveness by reducing cathepsin S expression. Moreover, sulforaphane increased microtubule-associated protein 1 light chain 3 (LC3) conversion, and the knockdown of LC3 by siRNA increased cell migration ability. Mechanistically, sulforaphane inhibited the cell motility of cervical cells through the extracellular signal-regulated kinase (ERK1/2) pathway, and blocking of the ERK1/2 pathway reversed autophagy-mediated cell motility and CTSS inhibition. In conclusion, sulforaphane exhibits antimetastatic activity against oral cancer cells by repressing cathepsin S through the ERK1/2 signaling pathway. Thus, cathepsin S and LC3 may be new targets for oral cancer treatment.
Citation Format: Chiao-Wen Lin, Chang-Tai Chen, Shun-Fa Yang. Sulforaphane suppresses metastasis via autophagic degradation of cathepsin S in oral cancer 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 4197.