bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2972: SPINK1, a soluble factor released by the therapy-damaged tumor microenvironment, promotes prostate cancer resistance
Authors: Chen Fei , Fu Da , Lam Eric , Sun Yu 
Published: July 2017

Abstract
Cancer evolution is driven by not only the genetic and/or epigenetic alterations of cancer cells, but also diverse factors that are derived from the surrounding tumor microenvironment (TME). Upon chemotherapy or radiation, stromal cells in the TME become senescent and develop a senescence-associated secretory phenotype (SASP) that is characterized by secretion of a large number of cytokines, chemokines, growth factors, and proteases. In most cases, the SASP is functionally regulated by the DNA damage secretory program (DDSP) and pathophysiologically responsible in vivo for disease exacerbation. We recently disclosed significant upregulation of the serine protease inhibitor Kazal type I (SPINK1) in primary normal human prostate fibroblasts after exposure to DNA damaging agents. SPINK1 plays critical roles in cancer cell proliferation, survival and motility in multiple human malignancies, but its influence as a soluble TME-associated factor on cancer progression remains unknown. In this study, we performed a series of molecular and cellular studies to define the biological roles of SPINK1 in an activated TME. Promoter analysis indicated that SPINK1 expression in the fibroblasts is regulated by multiple transcriptional factors including the NF-κB complex in response to genotoxic stress. Fibroblast-derived SPINK1 can significantly enhance the aggressiveness of prostate cancer cells including accelerated proliferation, increased migration, elevated invasion and more importantly, enhanced chemoresistance. SPINK1 triggers a typical epithelial-mesenchymal transition (EMT) in cancer cells, a process mediated by EGFR/PI3K/Akt and MAPK/Erk signaling pathways. Consistent with the in vitro data, our in vivo studies suggested that SPINK1 expression in the prostate TME substantially promoted cancer survival and disease progression. Clinical investigation revealed increased expression of SPINK1 in the stroma of multiple organ types including the prostate, lung and breast of cancer patients after chemotherapy, implying the systemic induction of SPINK1 by anticancer agents. Overall, our study demonstrates that SPINK1 is a soluble biomarker of therapeutically damaged TME and represents a potentially exploitable molecular target in human prostate cancer clinics.
Note: This abstract was not presented at the meeting.
Citation Format: Fei Chen, Da Fu, Eric Lam, Yu Sun. SPINK1, a soluble factor released by the therapy-damaged tumor microenvironment, promotes prostate cancer resistance [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 2972. doi:10.1158/1538-7445.AM2017-2972
Abstract 2976: Critical role of spatial location of hypoxia and its association with astrocytes in the resistance of brain tumor to therapy
Authors: Lin Chiu-Min , Chiang Chi-Shiun 
Published: July 2017

Abstract
Many reports have shown that hypoxia and gliosis could promote tumor cells by shielding from the immune response and relapsing, but their roles on brain tumor therapies are still unclear. Using an invasive murine astrocytoma tumor model, ALTS1C1, we found that tumor invasion front is associated with a specific hypoxia region, naming tumor peripheral hypoxia, contributes to brain tumor therapy resistant and may be responsible for tumor recurrence after the therapy. Using this tumor model, we found that the overgrowing tumor caused the shortage of vessels and resulted in the hypoxia in the early stage of tumor progression, which is conventionally called chronic hypoxia or avascular hypoxia. When tumor continues to grow, a rim of hypoxia area was formed at tumor edge and subsequently activated nearby astrocytes. At the same time, the outward reactive astrocytes enhanced tumor invasion into normal parenchyma tissues. As a result, a specific hypoxia was produced in tumor peripheral, which has relative high microvascular density (MVD) and is associated with highly reactive astrocytosis. We explored the role of this region on the response to therapies. By quantitative counting the apoptotic tumor cells across the tumor cross-section following radiation- or chemo-therapy, we found that cells at the active astrocytic region (the peripheral region) are more resistant than cells in tumor core. These results indicate that the peripheral hypoxia, not the chronic hypoxia, is the main cause of the failure of brain tumor therapy. Most importantly, we found that the formation of tumor peripheral hypoxia might be associated with the activation of astrocytes. Therefore, tactics that can suppress astrocytosis and prevent the formation of peripheral hypoxia may be alternative approaches for complementing the shortage of traditional brain tumor therapy.
Citation Format: Chiu-Min Lin, Chi-Shiun Chiang. Critical role of spatial location of hypoxia and its association with astrocytes in the resistance of brain tumor to therapy [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 2976. doi:10.1158/1538-7445.AM2017-2976
Abstract 2985: Interaction between the malignant melanoma cell of the primary lesion and the metastatic lesion
Authors: Hatano Takaharu , Motomura HIsashi , Fujikawa Heishiro , Yashiro Masakazu , Kitayama Kishu 
Published: July 2017

Abstract
Introduction: The prognosis of patients with malignant melanoma is extremely poor because of the frequent metastasis. We have occasionally experienced the clinical cases that malignant melanoma patients rapidly developed distant metastases after the surgical resection of primary cancer lesion. These cases suggested that a primary tumor may control a metastatic tumor. We hypothesized that primary melanoma cells might produce a factor(s) which regulate the progression of metastatic melanoma cells. Then we investigated the growth and invasion interaction between primary malignant melanoma cells and high metastatic melanoma cells. Materials and methods: We used two malignant melanoma cell lines, B16 as a parent primary melanoma cell line and a selected daughter cell line B16/BL6 with high metastatic ability. We investigated the invasive interaction between the parent B16 cells and daughter B16/BL6 cells in vitro. The conditioned medium from B16 cells and B16/BL6 cells was added to B16 cells or B16/BL6 cells. Then we examined the effect of these conditioned medium on the motility and proliferation of melanoma cells by MTT assay or invasion assay at 24 hours and 72 hours after the addiction of the conditioned medium. Results:The conditioned medium from B16 cells significantly (p=0.02) suppressed the invasion ability of B16/BL6 cells at 24 hours after the addiction of the conditioned medium. In contrast, the invasion ability of B16 cells were not affected by the conditioned medium from B16/BL6 cells at 24 hours. Each conditioned medium did not affect on the proliferation of both melanoma cell lines. On the other hand, at 72 hours after the addiction of the conditioned medium from B16 cells significantly (p=0.000003) suppressed the growth of B16/BL6 cells. Conclusion: Primary melanoma cells might down-regulate the progression of metastatic melanoma cells by a soluble factor(s).
Citation Format: Takaharu Hatano, HIsashi Motomura, Heishiro Fujikawa, Masakazu Yashiro, Kishu Kitayama. Interaction between the malignant melanoma cell of the primary lesion and the metastatic lesion [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 2985. doi:10.1158/1538-7445.AM2017-2985
Abstract 2998: Elotuzumab can costimulate NK cell responses by engaging SLAMF7
Authors: Pazina Tatiana , James Ashley Mentlik , MacFarlane Alexander W. , Bezman Natalie A. , Graziano Robert F. , Robbins Michael D. , Cohen Adam D. , Campbell Kerry S. 
Published: July 2017

Abstract
Elotuzumab (Elo) is an IgG1 monoclonal antibody targeting SLAMF7 (CS1, CRACC, CD319) protein, which is highly and uniformly expressed on multiple myeloma cells. Improved survival has been observed in multiple myeloma patients treated with Elo in combination with immunomodulatory drugs such as dexamethasone and lenalidomide. Previous work showed that the main mechanism of Elo action in vitro is CD16-mediated antibody dependent cellular cytotoxicity (ADCC) via Fc interaction with CD16 (FcγRIIIa) receptor on NK cells. However, SLAMF7 is also expressed on NK cells where it transmits an activating signal. We hypothesized that Elo can directly activate NK cells via SLAMF7 ligation. Utilizing non-fucosylated Elo that has higher affinity to CD16 and Elo mutant that has an Fc region mutation that abrogates binding to CD16, we confirmed that Elo promotes NK cell activation and degranulation in a CD16-dependent manner. Specifically, non-fucosylated Elo had higher potency, whereas Elo mutant did not stimulate degranulation or CD69 expression.
To test for co-stimulatory effects of Elo and Elo mutant we measured calcium signaling responses triggered by those antibodies in combination with antibodies to engage the activating receptors NKp46 and NKG2D. Elo or Elo mut alone had no effect on calcium signaling, but when added in combination with multimeric engagement of NKp46 and NKG2D both antibodies co-stimulated calcium signaling responses.
We conclude that Elo stimulates NK cells via interaction with CD16, but direct engagement with SLAMF7 can also transduce co-activating signals to potentiate calcium signals generated through NKp46 and NKG2D in a CD16-independent manner. Our results provide evidence that direct engagement with SLAMF7 by Elo has the potential to reduce the threshold of NK cell activation triggered through other activating receptors.
Citation Format: Tatiana Pazina, Ashley Mentlik James, Alexander W. MacFarlane, Natalie A. Bezman, Robert F. Graziano, Michael D. Robbins, Adam D. Cohen, Kerry S. Campbell. Elotuzumab can costimulate NK cell responses by engaging SLAMF7 [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 2998. doi:10.1158/1538-7445.AM2017-2998
Abstract 3012: Long-term aspirin use and total and cancer-specific mortality
Authors: Cao Yin , Stampfer Meir , Willett Walter , Spiegelman Donna , Manson JoAnn , Rimm Eric , Wang Molin , Ogino Shuji , Fuchs Charles , Giovannucci Edward , Chan Andrew 
Published: July 2017

Abstract
Background: Long-term follow of clinical trials of aspirin for the prevention of cardiovascular disease have shown that aspirin may be associated with a reduced risk of death from cancer, including colorectal, esophageal, and lung cancer, and possibly breast and prostate cancer. However, the potential benefits of aspirin use, at a range of doses and duration of use, on total and cancer-specific mortality have not been examined in large prospective cohort studies with long-term follow-up.
Methods: We examined the association between aspirin use and subsequent total and cancer-specific mortality, at a range of doses and duration of use, among 86,206 women in the Nurses' Health Study (1980-2012) and 43,977 men in the Health Professionals Follow-up Study (1986-2012). Participants with a history of cancer, heart disease, or stroke were excluded. Aspirin use was assessed at baseline and updated every 2 years with greater than 90% follow-up. Cox proportional hazards models were used to compute hazard ratios as estimates for age- and multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs).
Results: During up to 32 years of follow-up, 22,094 women and 14,749 men died, and 8,271 women and 4,591 men died of cancer. Compared with nonregular use, regular aspirin use was associated with lower risk of total mortality (multivariable-adjusted RR 0.93; 95% CI 0.90-0.95 for women and RR 0.89; 95% CI 0.86-0.93 for men), which was primarily due to a lower risk of dying from any cancer (RR 0.93; 95% CI 0.89-0.97 for women and RR 0.85; 95% CI 0.80-0.90 for men), especially colorectal cancers (RR 0.69; 95% CI 0.59-0.81 for women and RR 0.70; 95% CI 0.57-0.85 for men), breast cancers (RR 0.89; 95% CI 0.79-0.99), prostate cancers (RR 0.77; 95% CI 0.65-0.90), and lung cancers in men (RR 0.86; 95% CI 0.74-0.99). The benefit of aspirin on cancer mortality appeared evident with use of at least 0.5 to 1.5 standard aspirin tablets per week for both men and women; and the minimum duration of regular use associated with lower cancer mortality was 6 years.
Conclusions: Long-term aspirin use was associated with reduced risk of total mortality, primary due to reduced risk of dying from cancers.
Citation Format: Yin Cao, Meir Stampfer, Walter Willett, Donna Spiegelman, JoAnn Manson, Eric Rimm, Molin Wang, Shuji Ogino, Charles Fuchs, Edward Giovannucci, Andrew Chan. Long-term aspirin use and total and cancer-specific mortality [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 3012. doi:10.1158/1538-7445.AM2017-3012
Abstract 304: CLIC1 membrane insertion is a pivotal regulator of glioblastoma stem cell G1-S transition by promoting an increase of chloride permeability
Authors: Verduci Ivan , Carlini Valentina , Raciti Federica M. , Conti Matteo , Barbieri Federica , Florio Tullio , Mazzanti Michele 
Published: July 2017

Abstract
Glioblastoma (GBM) is the most aggressive and lethal brain tumor and, despite aggressive surgery and adjuvant radiotherapy and/or chemotherapy, the prognosis remains invariantly poor. As for most of solid and hematological malignancies, it was demonstrated that the bulk of tumor cells in GBM is generated by a rare fraction of self-renewing, multipotent cancer stem cells (CSCs) and the persistence of CSCs within the tumor mass is considered the main determinant of GBM development, progression, recurrence and radio- or chemoresistance. Thus, one of the main goals of current research is to identify specific biological mechanisms or intracellular pathways of CSCs whose pharmacological targeting might affect their survival and proliferation. In particular, little is known about the possibility that the molecular mechanisms underlying cell-cycle control in GBM CSCs are endowed with specific and unique features as compared with normal cells. Our study is based on the observation that GBM cells express higher levels of chloride intracellular channel 1 (CLIC1) as compared to nonmalignant brain cells and that in CSCs CLIC1 is mainly localized in the membrane forming an active channel. Conversely, in physiological conditions CLIC1 is mainly a cytoplasmic protein only transiently translocating to the membrane. We recently showed that the different level of activity of CLIC1 in CSCs and normal mesenchymal stem cells confers CLIC1-targeting drugs (for example the biguanide metformin) selective cytotoxicity toward tumor cells. Here we report, that in response to stress conditions, CLIC1 increases the probability to modify its structure going from a cytoplasmic hydrophilic form to a transmembrane conformation. Once in the membrane, CLIC1 acts as a chloride permeability, participating, together with NADPH oxidase, to the generation of a chronic state of oxidative stress that favor the transition between G1 and S phase. The peculiarity of CLIC1 exposure on the external face of the GMB CSC plasma membrane support the idea that this protein could represent a main determinant of the cell cycle progression in this tumor cell subpopulation and thus an accessible and relevant pharmacological target to eradicate CSCs in GBM.
Note: This abstract was not presented at the meeting.
Citation Format: Ivan Verduci, Valentina Carlini, Federica M. Raciti, Matteo Conti, Federica Barbieri, Tullio Florio, Michele Mazzanti. CLIC1 membrane insertion is a pivotal regulator of glioblastoma stem cell G1-S transition by promoting an increase of chloride permeability [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 304. doi:10.1158/1538-7445.AM2017-304
Abstract 3046: Identification of lncRNAs involved in regulation of androgen receptor splice variants in prostate cancer through CRISPR-Cas9-based screen
Authors: Ho Tsui-Ting , Koirala Pratirodh , Zhou Nanjiang , Mo Yin-Yuan 
Published: July 2017

Abstract
Prostate cancer is the second leading cause of death in men in the USA. Despite the high initial response rates to androgen deprivation therapy (ADT), these tumors ultimately develop the resistance, i.e., castration-resistant prostate cancer (CRPC). One of the contributing factors is constitutive expression of androgen receptor (AR) splice variants such as AR3, a major splice variant identified in clinical specimens. However, little is known about long non-coding RNAs (lncRNAs) on regulation of AR splicing. In this study, we generate CRISPR/Cas9-based libraries against a focus group of lncRNAs and an AR3 mini-gene reporter to identify lncRNAs involved in regulation of AR splicing. The principles of this screening system is that only sgRNAs capable of promoting AR3 expression will be enriched in SAM (Synergistic Activation Mediator) library, whereas these clones are lost from the knockout gRNA library after selection. This screen identifies several candidate lncRNA sgRNAs and dual gRNAs (targeting Lnc-DC/ Har1B/ LINC00568/ DHRS4-AS1/ SNHG5). Further characterization confirms the regulation of their corresponding endogenous genes and AR3 expression. Importantly, overexpression of Lnc-DC increases AR3 level and enhances tumor cell growth in response to androgen deprivation. Moreover, while ectopic expression of DHRS4-AS1 increases, DHRS4-AS1 knockout suppresses AR3. Finally, rescue experiments restore the ability of DHRS4-AS1 to induce AR3, further supporting a role for Lnc-DC and DHRS4-AS1 in AR3 regulation. Together, we demonstrate that the CRISPR/Cas9-based screening system provides a powerful tool for lncRNA research. As a result, these lncRNAs may serve as biomarkers to predict the response to ADT or therapeutic targets for treatment of CRPC.
Citation Format: Tsui-Ting Ho, Pratirodh Koirala, Nanjiang Zhou, Yin-Yuan Mo. Identification of lncRNAs involved in regulation of androgen receptor splice variants in prostate cancer through CRISPR-Cas9-based screen [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 3046. doi:10.1158/1538-7445.AM2017-3046
Abstract 3057: Gut microbiome controls liver metastasis
Authors: Ma Chi , Fu Qiong , Greten Tim 
Published: July 2017

Abstract
Aim: The gut microbiome can modify tumor immunity and has been suggested to be involved in the development of liver cancer. However, it remains unknown how the gut microbiome controls hepatic immune responses. This study was designed to exam the effect of the gut microbiome on liver antitumor immunity, and to study potential mechanism.
Experimental procedure: Antibiotic cocktail in drinking water was given to remove mouse gut microbiota. Control mice were kept on regular water. EL4 thymoma cells were injected s.c. to induce spontaneous liver metastasis. B16 melanoma and CT26 colon cancer cells were injected intrasplenically to form liver metastasis. Lung metastasis was induced by tail injection of tumor cells.
Results: Antibiotic cocktail efficiently depleted gut bacteria. Removing gut commensal bacteria did not affect the growth of primary s.c. tumors, but impaired formation of liver metastasis in different models. The inhibitory effect on liver metastasis by removing gut microbiome was found after intrasplenic injection of tumor cells to form liver metastasis using both B16 melanoma and CT26 colon cancer tumor cells. Interestingly, formation of lung metastasis caused by tail vein injection of B16 cells was not impaired by antibiotics treatment, suggesting a liver specific effect. The inhibition of liver metastasis by antibiotic treatment was absent in Rag1 knockout mice, suggesting that the mechanism is mediated by the adaptive immune system.
Conclusion: Our results suggest that the gut microbiome affects the liver immune microenvironment and modulates antitumor immunity.
Citation Format: Chi Ma, Qiong Fu, Tim Greten. Gut microbiome controls liver metastasis [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 3057. doi:10.1158/1538-7445.AM2017-3057
Abstract 3075: Analysis of microRNA profiles involved in the resistance to trifluridine
Authors: Tsunekuni Kenta , Koseki Jun , Konno Masamitsu , Asai Ayumu , Nishida Norihiro , Colvin Hugh , Kawamoto Koichi , Doki Yuichiro , Mori Masaki , Ishii Hideshi 
Published: July 2017

Abstract
Background: Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil, which was approved for the treatment of patients with metastatic colorectal cancer refractory to standard chemotherapies. A comprehensive analysis of miRNA profiles was performed in cell lines resistant to FTD established by ourselves, in order to explore the underlying mechanisms of resistance to the drug.
Method: We established subline resistance to FTD through continuous administration and increasing dose of the drug for 5 months using the colorectal cancer cell line DLD-1. Total RNA was extracted at intervals whilst establishing FTD resistant sublines, and miRNA expression was analyzed by microarray. The expression of miRNA that was significantly downregulated in the FTD resistant subline was knocked down to test its involvement in resistance to FTD. Cell viability was evaluated by crystal violet cytotoxicity test.
Results: The established FTD-resistant sublines showed more than 22-fold higher resistance to FTD and no cross-resistance to 5-FU. miRNA and mRNA clustered in the genome locus located in chromosome 9, 9p22.32 were downregulated in the FTD-resistant cell line, one of which was the miRNA let-7d-5p, which is one of the let-7 family and is known to target oncogenes and several key components of the cell cycle and cell proliferation. Anti-let-7d-5p treated DLD-1 was less sensitive to FTD than compared to control. The IC50 values of FTD were 16.8 µM and 7.6 µM for the anti-let-7d-5p treated cells and control respectively. On the other hand, overexpression of let-7d-5p in DLD-1 using let-7d-5p mimic increased the sensitivity to FTD compared to control. The IC50 values of FTD were 3.7 µM and 13.9 µM in the let-7d-5p overexpression cells and control respectively. 5FU sensitivity was only altered slightly in anti- let-7d-5p treated or let-7d-5p mimic treated cells. These data suggest that let-7d-5p is more relevant to sensitivity for FTD than that of 5FU.
Conclusion: Let-7d-5p expression level influenced FTD sensitivity more effectively than 5FU. It suggests that the let-7d-5p is a potential predictive marker for trifluridine/tipiracil treatment in the clinical setting.
Citation Format: Kenta Tsunekuni, Jun Koseki, Masamitsu Konno, Ayumu Asai, Norihiro Nishida, Hugh Colvin, Koichi Kawamoto, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Analysis of microRNA profiles involved in the resistance to trifluridine [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 3075. doi:10.1158/1538-7445.AM2017-3075