bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4774: Polyamines are rich and induces epigenetic change by inhibition of LSD1 in cancer stem-like cells
Authors: Tamari Keisuke , Ishii Hideshi , Konno Masamitsu , Nishida Naohiro , Koseki Jun , Kawamoto Koichi , Isohashi Fumiaki , Doki Yuichiro , Mori Masaki , Ogawa Kazuhiko 
Published: July 2017

Abstract
Cancer stem cells (CSC) are highly tumorigenic and resistant to chemotherapy and radiotherapy. We have previously reported that a small fraction of cancer cells with low proteasome activity had CSC-like properties. Ornithine decarboxylase (ODC) is an enzyme which converts ornithine to polyamines including putrescine, spermidine, and spermine. Proteasomal degradation of ODC is known to be ubiquitin-independent. The aim of this study was to explain how low proteasome activity gave CSC-like properties. Western blot showed high ODC protein level in CSC-like cells in cervical cancer and osteosarcoma cell lines, although ODC mRNA level is not high. These findings suggest that ODC protein level is high in CSC-like cells because ODC protein degradation is inactive. To investigate polyamine metabolism in CSC-like cells, we performed GC-MS analysis and found that putrescine, spermidine, and spermine were enriched in CSC-like cells. Furthermore, flux analysis showed conversion from ornithine to polyamines was more rapid in CSC-like cells. We performed a computational structure analysis and found that polyamines bind and inhibit demethylase site of LSD1 which is known to be a demethylase of histone H3K4 and a nuclear homolog of amine oxidases. Spermine was the strongest binding energy. An enzyme assay showed that LSD1 activity was dose-dependently inhibited by polyamines and spermine was the strong inhibitor. Finally, we analyzed performed ChIP sequencing analysis by using HeLa CSC-like cells and found that more global enrichment of H3K4me3 and less global enrichment of H3K4me1 than non-CSC-like cells. In conclusion, polyamines are rich in CSC, and be able to inhibit LSD1 activty and induce epigenetic alterations especially in H3K4 methylation in CSC.
Citation Format: Keisuke Tamari, Hideshi Ishii, Masamitsu Konno, Naohiro Nishida, Jun Koseki, Koichi Kawamoto, Fumiaki Isohashi, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa. Polyamines are rich and induces epigenetic change by inhibition of LSD1 in cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4774. doi:10.1158/1538-7445.AM2017-4774
Abstract 4778: Telomere DNA damage promotes mammary gland fibrosis and estrogen receptor-positive breast cancer
Authors: Wu Jianchun , Crowe David L. 
Published: July 2017

Abstract
Human breast luminal progenitor cells exhibit telomere DNA damage, which is associated with mammographic density and increased cancer risk. Telomeric repeat factor 2 (TRF2) protects telomeres from DNA damage response and its expression is reduced in human ductal carcinoma in situ and breast cancers. To determine the relationships between telomere DNA damage, mammary gland biology, and cancer risk we genetically deleted TRF2 expression in the mouse mammary gland. TRF2 conditional null mutant mice also were bred with tumor prone MMTV-Wnt1 animals. Telomere DNA damage response was determined by localization of 53BP1 at telomeres and activation of ATM/Chk2/p53 signaling by western blot. Mammary gland and tumor histopathology were determined by hematoxylin and eosin staining. Cell proliferation and ER+ differentiation was determined by immunohistochemistry. Tumor derived CD24+/CD49f+ mammary stem cells and CD61+ luminal progenitor cells were transplanted to mammary fat pads of immunodeficient mice. Alternative lengthening of telomeres was determined by PML localization at telomeres, chromosome orientation-fluorescence in situ hybridization, and telomere circular DNA amplification. Tumor bearing mice were injected with 15 mg raloxifene to determine mammary tumor anti-estrogen sensitivity. Mammary glands lacking TRF2 expression exhibited increased telomere DNA damage response, histopathological and functional degeneration, and prominent ductal fibrosis. TRF2 deficient mammary tumors exhibited rapid onset and increased proliferation. Tumor derived LP cells failed to form tumors following transplantation. The MSC population was highly tumorigenic and maintained telomeres via the ALT mechanism. Telomere DNA damage response in mammary tumors resulted in p53 dependent ER+ cellular differentiation and sensitivity to anti-estrogen therapy. Telomere DNA damage correlated with estrogen receptor expression in human breast cancer. We concluded that telomere DNA damage resulted in mammary gland fibrosis, reduced tumor latency, ER+ differentiation, and sensitivity to anti-estrogen therapy.
Citation Format: Jianchun Wu, David L. Crowe. Telomere DNA damage promotes mammary gland fibrosis and estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4778. doi:10.1158/1538-7445.AM2017-4778
Abstract 4779: Targeting the CCL20-CCR6 axis as a novel opportunity to stimulataneously modulate cancer stem cells and the tumor-immune infiltrate by a dual anti-cancer mechanism
Authors: Vlerken-Ysla Lilian E. van , Rios-Doria Jonathan , Moynihan James , Shan Lu , Hollingsworth Robert E. , Herbst Ronald , Hurt Elaine M. 
Published: July 2017

Abstract
Drugs that target cancer stem cells (CSCs) are thought to be a critical component of any successful therapy against cancer. CSCs are responsible for chemoresistance, metastasis, and ultimately relapse of the cancer, even after an initial successful therapeutic intervention. While it is well known that CSCs are driven by some of the same major self-renewal pathways that drive embryonic stem cells, knowledge of other cellular pathways that drive CSC activity is still limited. In this work, we uncover a novel role for chemokine (C-C motif) ligand 20 (CCL20) in CSC growth and activity, expanding the role for this chemoattractant protein. We discovered that CSCs of many tumor types overexpress CCL20, which we show drives CSC self-renewal and proliferation by autocrine signaling through its receptor CCR6. Targeting this axis with a neutralizing monoclonal antibody against CCL20 significantly reduces CSC frequency and tumor initiation and growth, supporting the novel therapeutic potential of targeting the CCL20-CCR6 axis as a strategy to eliminate CSCs. Furthermore, we found that CCL20 secreted by tumor cells also strongly influences the frequencies not only of T-cells, particularly immune-suppressive regulatory T-cells (Treg) and Th17 populations, but also dendritic and neutrophil/gMDSC populations, to promote anti-tumor immunity that leads to immune-mediated inhibition of tumor growth. Strikingly, we discovered that tumor-specific CCL20 impacted not just the immune cell balance within the tumor microenvironment, but had far reaching effects into the peripheral immune system as well. Thus, our overall findings propose that CCL20 plays a dual role in the tumor environment: 1) by driving activity and tumorigenic ability of CSCs, and 2) by promoting an immunosuppressive phenotype. In this work we show that therapeutic neutralization of CCL20 can deliver a one-two punch against cancer, by directly inhibiting CSCs, and by relieving immunosuppression, thereby opening this target up as an exciting novel strategy to treat cancer.
Citation Format: Lilian E. van Vlerken-Ysla, Jonathan Rios-Doria, James Moynihan, Lu Shan, Robert E. Hollingsworth, Ronald Herbst, Elaine M. Hurt. Targeting the CCL20-CCR6 axis as a novel opportunity to stimulataneously modulate cancer stem cells and the tumor-immune infiltrate by a dual anti-cancer mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4779. doi:10.1158/1538-7445.AM2017-4779
Abstract 4780: Crucial role of S100A14 in blocking cancer stem cells and sensitizing to chemotherapy through STAT3 destabilization in human colorectal cancer
Authors: Cho Jaebeom , Min Hye-Young , Lee Ji-Sun , Lee Ho-Young 
Published: July 2017

Abstract
Colorectal cancer (CRC) is a major type of human cancers in terms of incidence and mortality worldwide. Chemotherapy is one of the standard protocols for the treatment of CRC but drug resistance is recognized as the main cause of treatment failure. Resistance to anticancer therapy is a multifactorial event involving a number of interrelated or independent mechanisms. Growing evidence supports a critical role of cancer stem cell (CSC) in development, progression, and resistance to anticancer therapies in CRCs. However, the molecular and cellular mechanisms underlying the CSC's chemoresistance are not completely defined, and a comprehensive understanding of the biology of the CSCs is urgently needed. We have investigated mechanisms of chemoresistance, focusing on those mediated by CSCs, through the employment of CRC stem-like cell populations that are: 1) sorted out by using well-characterized stemness markers; ii) established via serial passage through increasing doses of oxaliplatin or 5-FU; or iii) enriched by culturing in sphere forming condition. We then assessed changes involved in CSC maintenance and found a novel role of S100A14 in CSCs of CRC. We found that transcriptional down-regulations of S100A14 expression conferred phenotypes of CSCs in the stem-like cell populations of CRC. Consistently, elevation of S100A14 expression sensitized the stem-like cell populations to the treatment with 5-FU in vitro and in vivo. Mechanistically, S100A14 directly interacted with STAT3 and promoted its degradation via the ubiquitin-proteasome pathway, leading to decreases in STAT3 target gene expression and colony forming capacity of the stem-like cell populations. Further, S100A14 expression was markedly downregulated in human CRC tissue specimens compared with their normal counterparts. Moreover, the expression level of S100A14 was inversely correlated with clinical outcomes in patients with CRC. These results collectively suggest that S100A14 is a novel target for the treatment of colorectal cancer by targeting CSCs.
Citation Format: Jaebeom Cho, Hye-Young Min, Ji-Sun Lee, Ho-Young Lee. Crucial role of S100A14 in blocking cancer stem cells and sensitizing to chemotherapy through STAT3 destabilization in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4780. doi:10.1158/1538-7445.AM2017-4780
Abstract 4783: Regulation of GBM stemness and mesenchymal transition
Authors: Chow Kin-Hoe , Park Hee Jung , George Joshy , Chen Yuanxin , Gallup Andrew , Jiang Wen , Kim Betty Y. , Yun Kyuson 
Published: July 2017

Abstract
While growing evidence suggests that tumor microenvironment can modulate stemness and the mesenchymal phenotype, little is known about how these cell states are coordinately regulated. We report that S100A4 controls both stemness and mesenchymal transition in GBM cells. In a spontaneous mouse glioma model and in primary human GBM tumorspheres, S100A4 expression is enriched in tumor-initiating cells and is required for self-renewal and tumor growth in vivo. In addition, greater than 80 percent of S100A4+ cells are associated with the tumor vasculature, a known niche for glioma stem cells, and S100A4 promotes pro-angiogenic factor expression. Interestingly, acidosis induces expression of S100A4 and the EMT regulators SNAIL1/2 and acidosis-induced EMT regulator expression requires S100A4 function. Importantly, S100A4 functions as a molecular switch between the proneural and mesenchymal states in GBM as S100A4 knockdown results in down-regulation of the mesenchymal signature genes, including the “master transcriptional regulators of mesenchymal transition”, and concurrent up-regulation of proneural signature genes. Together, these results indicate that S100A4 sits in a critical node in the molecular network that controls both glioma stem cells and the mesenchymal phenotype.
Citation Format: Kin-Hoe Chow, Hee Jung Park, Joshy George, Yuanxin Chen, Andrew Gallup, Wen Jiang, Betty Y. Kim, Kyuson Yun. Regulation of GBM stemness and mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4783. doi:10.1158/1538-7445.AM2017-4783
Abstract 4784: Regulation of ovarian cancer stem cell population by DDB2
Authors: Cui Tiantian , Srivastava Amit Kumar , Han Chunhua , Gao Zhiqin , Zhang Xiaoli , Wani Altaf A. , Wang Qi-En 
Published: July 2017

Abstract
Cancer stem cells (CSCs), representing the root of many solid tumors including ovarian cancer, have been implicated in disease recurrence, metastasis, and therapeutic resistance. Our previous study has demonstrated that DNA damage-binding protein 2 (DDB2) is able to reduce the abundance of CSCs in the bulk ovarian cancer cells, providing a novel mechanism to explain the DDB2-mediated suppression of tumorigenicity and metastasis, and also suggesting that low expression of DDB2 is required for the maintenance of CSCs. However, the underlying mechanisms still remain unclear. By using the Tet-On DDB2 modulation system, we have confirmed our previous finding that downregulation of DDB2 expands the CSC population in the 2008 ovarian cancer cell line. We also found that DDB2 is able to suppress non-CSC-to-CSC conversions in this cancer cell line. DDB2 has been recognized as a transcriptional regulator. Our microarray analysis has identified ALDH1A1 to be targeted and regulated by DDB2. The downregulation of ALDH1A1 expression by DDB2 at both mRNA and protein levels has been validated in various ovarian cancer cell lines. The mechanistic investigation demonstrated that DDB2 can bind to the promoter region of the ALDH1A1 gene, facilitating the enrichment of histone H3K27me3 by recruiting EZH2 to the promoter region, eventually inhibiting the promoter activity of the ALDH1A1 gene. In addition, we also found that DDB2 competes with transcription factor C/EBPβ for binding to the ALDH1A1 promoter, indirectly inhibiting the ALDH1A1 promoter activity. Finally, we knocked down the expression of DDB2 and ALDH1A1 individually or simultaneously in the 2008 ovarian cancer cell line, and analyzed their tumorigenicity. We found that downregulation of ALDH1A1 is able to block DDB2 silencing-induced expansion of the CSC population, indicating that ALDH1A1 plays a critical role in DDB2-mediated suppression of the CSC population in ovarian cancer cells. In summary, our data demonstrated that DDB2, functioning as a transcription repressor, is able to abrogate ovarian CSC properties by downregulating ALDH1A1 expression. This study provides a novel mechanism underlying the regulation of the CSC population, and would facilitate the development of efficient strategies for eliminating CSCs to prevent tumor relapse and metastasis in ovarian cancers. (Supported by NIH R01CA151248)
Citation Format: Tiantian Cui, Amit Kumar Srivastava, Chunhua Han, Zhiqin Gao, Xiaoli Zhang, Altaf A. Wani, Qi-En Wang. Regulation of ovarian cancer stem cell population by DDB2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4784. doi:10.1158/1538-7445.AM2017-4784
Abstract 4786: Integrated eoxme and transcriptome sequencing identifies a novel candidate for breast cancer
Authors: Lee Kyung-Min , Noh Dong-Young , Han Wonshik 
Published: July 2017

Abstract
Many somatic mutations, structural alterations, and gene expression changes are causally implicated in oncogenesis and tumor progression, and as a result, affect clinical outcome. Although majority of breast cancer patients have benefits from therapeutics targeting tumor biology still many patients suffer from disease recurrence and metastasis. To find novel therapeutic target in breast cancer, here we examine the both whole exome and whole transcriptome of fresh-frozen primary breast cancer tissues from 120 patients whose clinical, pathological, and survival data are available. We identified 11,684 putative somatic mutations in 7,373 genes. We hypothesized that therapeutic target has to have recurrent mutation and gene expression at least more than average expression. With a cut-off of 3 or more mutations in each gene, 1,116 genes were selected. After the filtering of Volume&gt;0.3, 696 genes were selected. Finally, 55 genes were selected which are druggable or potentially druggable using drug database. Interestingly, 18 of the 55 were genes involved in metabolism. Among them we further focused PSMD2 and interrogated their oncogenic roles, a subunit of the 19S regulatory complex of proteasomes, as a constituent of a signature is a candidate driven factor in breast cancer. PSMD2 is required for proliferation both in vitro and in vivo, as shRNA-mediated PSMD2 silencing attenuated tumor growth. Further, PMSD2 is sufficient to induce stem cell characteristics, as forced PSMD2 expression facilitated mammosphere formation and increased the CD44+ breast CSC-like population. Mechanistically, PSMD2 inhibition were associated with changes in epithelial-mesenchymal transition (EMT) phenotype. Knockdown of PSMD2 induced dramatic morphological changes, the typical spindle-like appearance cells were replaced with the round shape, like epithelial morphology. Moreover, treatment of TGF-β1, the main inducer of EMT, lead to increased expression of PSMD2. PSMD2 silencing up-regulated E-cadherin and down-regulated expression of vimentin, N-cadherin and snail, mesenchymal markers. Clinically, PSMD2 expression was elevated in basal-like TNBC (triple negative breast cancer), correlated with poor prognosis, insilico analysis on a dataset comprising over 2413 microarrays of the web application bc-GenExMiner. Altogether, our findings suggest that PSMD2 may be a good molecular target candidate and PSMD2 inhibitor may kills breast cancer stem cells and ameliorates poor prognosis of breast cancer.
Citation Format: Kyung-Min Lee, Dong-Young Noh, Wonshik Han. Integrated eoxme and transcriptome sequencing identifies a novel candidate for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4786. doi:10.1158/1538-7445.AM2017-4786
Abstract 4790: Let-7 mediates sulindac inhibition of tumor cell transformation
Authors: Liang Zhipin , Yi Bin , Zhao Hongyou , Ma Ruixia , Xi Yaguang 
Published: July 2017

Abstract
Cell transformation is the process in which normal cells acquire the properties of cancer. Sulindac Sulfide (SS) is one of non-steroidal anti-inflammatory drugs (NSAIDs), and its anticancer activity in prevention of tumor occurrence and progression has been documented in various human cancers. In this study, we observed the anti-transformative activity of SS in NIH/3T3 cells by using a two-stage transformation assay induced by the carcinogens, 3-methylcholanthrene (MCA) and 2-O-tetradecanoylphorbol-13-acetate (TPA) in which foci formation is used to characterize the transformed cells. We found that SS could inhibit foci formation by attenuation of TPA’s promotive effect. K-Ras was upregulated in the transformed cells, while SS treatment could selectively inhibit the growth of transformed cell in which K-Ras was suppressed significantly. Loss-of-function study demonstrated that knockdown of K-Ras in NIH/3T3 cells could significantly reduce foci formation, which support that K-Ras might be one of the key targets involved in SS inhibiting tumor cell transformation. When studying the mechanism by which SS regulates K-Ras, we triggered tumor suppressor miRNA, let-7b, which was previously reported to target K-Ras and repress its expression through the post-transcriptional or translational modulation. We found that let-7b could be upregulated in the transformed cells by SS treatment. However, the inhibitory effect of SS on foci formation was significantly attenuated when let-7b was knocked down by CRISPR/Cas9. In parallel, K-Ras maintained static expression in the transformed cells, regardless of SS treatment. Meanwhile, the overexpression of endogenous let-7b can significantly inhibit tumor transformation. In addition, we demonstrated that SS could suppress the expression of Lin28 that interacts with let-7 through a documented feedback loop. Given our previous studies reporting that SS was able to inhibit the transcriptional activity of NF-κB that is involved in regulation of Lin28 expression, our study demonstrates that the NF-κB/Lin28/Let-7/K-Ras axis addresses a new mechanism responsible for anti-transformative activity of SS. These results will provide novel insights into understanding the mechanisms involved in tumorigenesis and benefiting identification of new targets for drug development in prevention of tumor progression.
Citation Format: Zhipin Liang, Bin Yi, Hongyou Zhao, Ruixia Ma, Yaguang Xi. Let-7 mediates sulindac inhibition of tumor cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4790. doi:10.1158/1538-7445.AM2017-4790
Abstract 4793: TRAF2 is required for the survival of ErbB2-transfored mammary tumor cells
Authors: Habelhah Hasem , Fan Yumei , Zhang Laiqun 
Published: July 2017

Abstract
TRAF2 regulates signaling pathways downstream of many members of the TNF receptor superfamily, such as TNFR1 and CD40. Recently, we found that TRAF2 also plays an important role in breast cancer cell survival under conditions of endoplasmic reticulum (ER) stress. It is known that TRAF2 knockout (KO) mice die within a week of birth and this lethality can be rescued by KO of TNFα or TNFR1. In order to determine the role of TRAF2 in mammary tumor development and progression, we crossed MMTV-ErbB2 mice (FVB) with TNF-/-/TRAF2-/+ mice (B6), and generated MMTV-ErbB2 (ErbB2), MMTV-ErbB2-TNF-/- (ErbB2/T-KO) and MMTV-ErbB2-TNF-/-/TRAF2-/- (ErbB2/T/T2-DKO) mice all in FVB/B6 mixed background. In 43 weeks, only 1 of 10 ErbB2/T/T2-DKO mice developed a mammary tumor, while 50% of ErbB2 and ErbB2/T-KO mice developed multiple and larger tumors in 30-32 weeks. Interestingly, the tumor derived from the ErbB2/T/T2-DKO mice did not show decreased cyclin D1 expression, nor the tumor cells cultured in vitro show decreased NF-κB activation in response to RANKL. In addition, ErbB2/T/T2-DKO cells formed mammospheres of similar appearance with that of ErbB2 cells in HEMA-coated plates. However, after dispersion of the mammospheres into single cells, ErbB2/T/T2-DKO cells formed dead cell aggregates, while ErbB2 and ErbB2/T-KO cells formed secondary mammospheres, suggesting that the self-renewal capacity of ErbB2/T/T2-DKO cells is impaired. Mechanistic studies reveal that ErbB2/T/T2-DKO cells are sensitive to death caused by ER stress but not by TRAIL or DNA damage, and that this sensitivity is significantly inhibited by knockdown of RIP1. Collectively, these findings suggest that TRAF2 plays a critical role in mammary tumor development and progression by suppressing the pro-death activity of RIP1, and that TRAF2 and RIP1 interaction could be an attractive target for development of new anti-breast cancer drugs.
Citation Format: Hasem Habelhah, Yumei Fan, Laiqun Zhang. TRAF2 is required for the survival of ErbB2-transfored mammary tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4793. doi:10.1158/1538-7445.AM2017-4793