tbuckley/cabot-search huggingface dataset:
Abstract 4632: Exosome-mediated transfer of miR-183-5p from tumor cells to macrophages contributes to regulate TAMs phenotypes and promote tumor progression and metastasis
Authors: Jian Guo, Wei Wang, Yan Liu, Huiwen He, Chen Zhang, Chong Chen, Yunping Luo
Journal: Cancer Research (2017)

Abstract Tumor-associated macrophages (TAMs) perform supportive roles in promoting tumor progression and metastasis. In tumor microenvironment, the phenotypes of TAMs are regulated by a variety of factors, such as cytokines, ligends and products of metabolism. Recently, Exosome-mediated transfer of miRNAs is proved to be a significant way for intercellular communications. Whether exosomal miRNAs derived from tumor cells contribute to TAMs’ phenotypes remains unclear. In this study, we aim to identify the miRNAs in exosomes transferred from tumor cells to macrophages and explore how these miRNAs regulate the TAMs phenotypes. In the beginning we transferred CY3-labled miRNA NC to 4T1 mouse breast cancer cells and then co-cultured with bone marrow-derived macrophages (BMDMs). The CY3 fluorescence could be observed in BMDMs after 48 hour, suggesting that miRNAs could be transferred from tumor cells to macrophages. Next, we performed miRNAs sequencing in either BMDM or exosomes derived from 4T1 cancer cells. We analyzed and compared the miRNAseq data by bio- informatics and found that there were 30 of the most abundant miRNAs in 4T1 exosomes, and nearly all of which were rich in BMDMs. However, it was found interestingly that miR-183-5p was extremely low in BMDMs. Furthermore, we treated BMDMs with exosomes isolated form 4T1 cell conditioned medium, and then we found importantly the miR-183-5p in BMDMs was increased significantly, while cultured with exosome-depleted 4T1 conditioned medium, the expression of miR-183-5p in BMDMs was not changed. Meanwhile, we isolated TAMs from 4T1 mouse breast tumor while spleen macrophages from normal mouse as a control. The expression of miR-183-5p in TAMs was much higher than that in spleen macrophages. Moreover, it was determined that expression of pro-inflammatory cytokine TNF and IL-6 in BMDM were increased significantly in BMDMs treated with 4T1-derived exosomes. Correspondingly, transferred miR-183-5p mimic into BMDMs, the expression of TNF and IL-6 were also increased. Finally we co-cultured 4T1 cells with BMDMs transferred with miR-183-5p, and the migration and invasion of 4T1 cells were significantly enhanced. Taken together, our study demonstrate that miR-183-5p that high expression in 4T1 exosomes can transferred into macrophages to regulated their phenotypes and promote tumor progression and metastasis in breast tumor microenvironment. Citation Format: Jian Guo, Wei Wang, Yan Liu, Huiwen He, Chen Zhang, Chong Chen, Yunping Luo. Exosome-mediated transfer of miR-183-5p from tumor cells to macrophages contributes to regulate TAMs phenotypes and promote tumor progression and 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 4632. doi:10.1158/1538-7445.AM2017-4632
Abstract 4563: Local and abscopal effects in oncolytic virotherapy are boosted by immune checkpoint blockade, immunogenic chemotherapy, or IFNAR blockade
Authors: Laetitia Fend, Takahiro Yamazaki, Xavier Préville, Eric Quéméneur, Oliver Kepp, Julien Adam, Aurélien Marabelle, Jonathan Pitt, Guido Kroemer, Laurence Zitvogel
Journal: Cancer Research (2017)

Abstract Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We here report that an engineered oncolytic Vaccinia Virus, VVWR-TK-RR--Fcu1, is able to induce an immunogenic cell death and thus to generate a systemic immune response. Effect on tumor growth and survival is largely driven by CD8+ T-cells, and we could demonstrate that the immune cell infiltrate in the tumor could be reprogrammed towards a higher ratio of effector T-cells to regulatory CD4+ T-cells. The key role of the type 1-IFN pathway in oncolytic virotherapy was also highlighted, and we could show a strong abscopal response in Ifnar-/- tumors. In this model, the single administration of the virus directly into the tumors, on one flank, led to regression in the contralateral flank (i.e. opposite to the virus injection site). Moreover, we observed that these effects are further enhanced when the oncolytic treatment is combined with either immunogenic chemotherapy such as oxaliplatin, or with immune checkpoint blockers such as anti-PD-1 or anti-CTLA-4. Altogether, these data suggest that local oncolytic virotherapy in patients with tumors altered in IFNAR signaling could increase immune-mediated abscopal regression of distant metastases. Citation Format: Laetitia Fend, Takahiro Yamazaki, Xavier Préville, Eric Quéméneur, Oliver Kepp, Julien Adam, Aurélien Marabelle, Jonathan Pitt, Guido Kroemer, Laurence Zitvogel. Local and abscopal effects in oncolytic virotherapy are boosted by immune checkpoint blockade, immunogenic chemotherapy, or IFNAR blockade [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 4563. doi:10.1158/1538-7445.AM2017-4563
Abstract 5616: Activation of CD137/CD137L results in reduced tumor cell proliferation in human colon cancer
Authors: Tanja Grimmig, Simone Callies, Hannes Naegele, Martin Wagner, Romana Moench, Buelent Polat, Christoph-Thomas Germer, Martin Gasser, Ana Maria Waaga-Gasser
Journal: Cancer Research (2017)

Abstract Background: CD137L is expressed on antigen presenting cells and CD137/CD137L interaction co-stimulates activation and proliferation of CD137 expressing T cells. CD137L expression has also been detected on various cancer cells. While signaling in immune cells showed both inhibiting and activating effects the impact of CD137L induction on tumor cells is poorly understood. In this study, the expression of CD137 and CD137L and the effects of CD137L activation were analyzed in human colorectal cancer (CRC). Methods: Expression of CD137 and CD137L was examined in human colon cancer cell lines HT29, SW480 and SW620 treated with or without hypoxia using RT-qPCR, Western blot and FACS analysis. Its differentiated expression was further analyzed in human CRCs by immunofluorescent double-staining. To dissect the effects of CD137L activation on cancer cells, MTS proliferation assays were additionally performed. Results: All three human colon cancer cell lines demonstrated high cellular (FACS) and protein (Western Blot) CD137L expression. CD137 was found only in SW480 cells at weak expression. Additionally, both CD137 and CD137L were significantly upregulated in cells treated with hypoxia. In human CRCs both CD137 and CD137L expressing tumor cells were detected by immunofluorescent double-staining. Interestingly, activation of CD137L by immobilized CD137-Fc resulted in reduced cancer cell proliferation compared to IgG1-Fc controls. Conclusion: Our results demonstrate tumor cell mediated expression of the costimulatory molecule CD137 and its ligand CD137L in both colon cancer cell lines and human colorectal cancer. Moreover, CD137L reverse signaling was found to reduce cancer cell proliferation in vitro. Based on these data, the CD137/CD137L signaling pathway seems to present a promising target for cancer therapy in CRC. Note: This abstract was not presented at the meeting. Citation Format: Tanja Grimmig, Simone Callies, Hannes Naegele, Martin Wagner, Romana Moench, Buelent Polat, Christoph-Thomas Germer, Martin Gasser, Ana Maria Waaga-Gasser. Activation of CD137/CD137L results in reduced tumor cell proliferation in human colon 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 5616. doi:10.1158/1538-7445.AM2017-5616
Abstract 1869: Improved image-guided surgical resection of glioblastoma with [18F]-fluoroethyltyrosine Cerenkov luminescence imaging
Authors: David Y. Lewis, Richard Mair, Alan J. Wright, Kieren Allinson, Scott K. Lyons, Tom Booth, Robert Bielik, Dmitry Soloviev, Kevin M. Brindle
Journal: Cancer Research (2017)

Abstract The ability of a surgeon to completely resect a tumor is directly related to outcome in high- and low-grade gliomas. However current intraoperative navigational tools are useful only in a subset of glioma patients and do not detect the full extent of disease. We modelled orthotopic brain tumors by stereotactically implanting human U87, rat F98 and C6 glioblastoma cells into the forebrains of rats. We show here that a new hybrid PET-Cerenkov luminescence imaging approach using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) can accurately delineate tumor margins pre- and intra-operatively. We demonstrate consistency in the successful localisation and quantification of tumor burden using PET and Cerenkov luminescence imaging. The Cerenkov signal in individual tumors was directly proportional to the signal detected in corresponding FET PET scans (y = 1.06x - 0.01; R2 = 0.98; p &amp;lt; 0.0001) and subsequent autoradiography indicated equivalence between modalities. Cerenkov luminescence was better able to discriminate tumor from healthy brain tissue than the current ‘gold standard’ for intraoperative mapping, 5-ALA (5-aminolevulinic acid), indicated by a greater area under the ROC curve in human xenograft (0.968 ± 0.003 vs. 0.893 ± 0.019; p = 0.003) and syngeneic rat glioma models (0.970 ± 0.010 vs. 0.774 ± 0.046; p = 0.006). The quantitative accuracy of Cerenkov luminescence enabled us to determine a threshold of 2.1 x 102 p-1 sec-1 cm-2 sr-1 MBq-1 that separated U87 human glioblastoma and normal brain tissue, more precisely guiding tumor excision than 5-ALA. At the optimal threshold the specificity for detecting syngeneic rat and human xenograft gliomas was better with FET Cerenkov than 5-ALA (91.1 ± 2.7 % vs. 67.2 ± 5.2 %; p = 0.007 and 91.2 ± 1.0 % vs. 82.9 ± 1.8 %; p = 0.005 respectively). We confirmed and extended these findings at higher spatial resolution on cryosections using FET autoradiography and 5-ALA confocal microscopy, with FET demonstrating higher specificity and sensitivity for tumor detection than 5-ALA. FET PET-Cerenkov luminescence imaging has the potential for guiding resections in a much broader range of glioma patients than current approaches. Previous clinical experience with FET offers a facile route for clinical translation of this technology. Citation Format: David Y. Lewis, Richard Mair, Alan J. Wright, Kieren Allinson, Scott K. Lyons, Tom Booth, Robert Bielik, Dmitry Soloviev, Kevin M. Brindle. Improved image-guided surgical resection of glioblastoma with [18F]-fluoroethyltyrosine Cerenkov luminescence imaging [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 1869. doi:10.1158/1538-7445.AM2017-1869
Abstract 1929: A novel orthotopic mouse model in sarcomas
Authors: Silvia Garcia Monclús, Juan Huertas Martínez, Laura Lagares Tena, Santiago Rello Varona, Olga Almacellas Rabaiget, David Herrero Martin, Roser López Alemany, Oscar Martinez Tirado
Journal: Cancer Research (2017)

Abstract Pediatric sarcomas are a heterogeneous group of bone and soft tissue malignancies affecting children and young adults. One of the most important prognostic factors of those diseases is the presence of metastasis at diagnosis. In that context, we have developed a novel orthotopic model which consists in injecting Ewing Sarcoma (ES) or Rhabdomyosarcoma (RMS) tumor cells at the gastrocnemius muscle of mice and extracting the tumor at a of 10 mm x 13 mm volume. After surgery, animals maintain a complete functional extremity and can live until lung metastasis detection (about 60 days post-injection). Moreover, we have validated the suitability of the model with an Ewing Sarcoma EphA2-low expression cell line. Epha2 is a tyrosine kinase receptor that has been found overexpressed in a wide variety of tumors and correlated with malignant phenotype. In this study we report that EphA2 receptor is phosphorylated at S897 in a panel of ES cell lines, which is related to the oncogenic properties of the receptor. Stable silencing of EphA2 in two different ES cell lines resulted in a decrease in the clonogenic, proliferation, migration and invasion capacity in vitro. Moreover, we performed an experimental metastasis assay, injecting tumor cells through the tail vain of mice and observed a reduction in the lung metastasis incidence in EphA2 silenced cells. We then used this new orthotopic metastasis model to validate the impairment in the invasion capacity of EphA2 silenced cells and confirm the decrease in lung metastasis incidence, indicating an oncogenic role for EphA2 in ES. This novel orthotopic metastasis model is a valuable tool both for the study of spontaneous metastasis and also for evaluating therapeutic index in the onset of metastasis, which can also be applied to the study of other pedriatric sarcomas. Citation Format: Silvia Garcia Monclús, Juan Huertas Martínez, Laura Lagares Tena, Santiago Rello Varona, Olga Almacellas Rabaiget, David Herrero Martin, Roser López Alemany, Oscar Martinez Tirado. A novel orthotopic mouse model in sarcomas [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 1929. doi:10.1158/1538-7445.AM2017-1929
Abstract 465: Downregulation of miR-193a and its correlation with clinical and pathological behavior of colorectal cancer
Authors: Afraa M. Mamoori, Riajul Wahab, Farhadul Islam, Katherine Lee, Robert A. Smith, Vinod Gopalan, Alfred Ky Lam
Journal: Cancer Research (2017)

Abstract Aim: Deregulation of miR-193a expression was reported to have significant roles in cancer development and progression. This study aimed to investigate the expression pattern and clinicopathological implication of miR-193a-3p in patients with colorectal cancer. Also, the bio-physiological effects of miR-193a in colon cancer cells were examined. Methodology: Fresh frozen tissues from 70 matched colorectal cancers (adenocarcinomas) and adjacent noncancer tissue were prospectively collected with no selection bias. Expression level of miR193a-3p was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical staining was used to detect the expression level of K-ras protein as a predicted downstream target for miR-193a. Restoration of the miR-193a level in the cell lines was achieved by permanent transfection. Multiple functional and immunological assays were performed to analyze miR-193’s cellular implications and target affinity in colon cancer cell lines. Results: Downregulation of miR-193a-3p was noted in the majority of the colorectal cancer tissues when compared to nontumor colorectal tissues (70%, n= 49/70). In addition, high prevalence of miR-193a downregulation was noted in early stage colon cancer tissues and cell lines (SW480) when compared to advanced staged colorectal carcinomas. Immunohistochemical analysis revealed inverse correlation between miR-193a and K-ras expression in which high K-ras protein expression was reported in 28/49 cases with miR-193a downregulation. Analogues findings were also observed in cell lines using Western blot (P value&amp;lt; 0.05). Overexpression of miR-193a in colon cancer cell lines resulted in reduced cell proliferation, increased apoptosis and a less accumulation of cells in the G0-G1 phase cell cycle. Conclusion: The current study confirms the downregulation of miR-193a-3P in colorectal cancer and its tumour suppressor effects in vitro plays a key role in the modulation of K-ras regulated molecular signalling pathways in colon cancers Note: This abstract was not presented at the meeting. Citation Format: Afraa M. Mamoori, Riajul Wahab, Farhadul Islam, Katherine Lee, Robert A. Smith, Vinod Gopalan, Alfred Ky Lam. Downregulation of miR-193a and its correlation with clinical and pathological behavior of 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 465. doi:10.1158/1538-7445.AM2017-465
Abstract 2276: Effect modification by isoflavones on the association between salt intake and gastric cancer risk: A case-cohort study within the Korean multi-center cancer cohort
Authors: Jieun Jang, Yunji Hwang, Choonghyun Ahn, Kwang-Pil Ko, Aesun Shin, Keun-Young Yoo, Sue K. Park
Journal: Cancer Research (2017)

Abstract Backgrounds: Attenuation by genistein, an isoflavone abundant in soybean, of gastric carcinogenesis induced by sodium chloride was reported in an animal study. Up to date, role of isoflavone as an effect modifier on the association between salt intake and gastric cancer risk is not clearly established. Methods: We randomly selected 640 subcohort subjects without cancer history at enrollment from the Korean multi-center cancer cohort participants. Ninety-nine gastric cancer cases were identified from the inside (N=8) and the outside (N=91) of the subcohort after the 12.2 years of median follow-up time. To estimate individual’s salt intake, we measured 24-hour urinary sodium excretion from spot urine using the Tanaka’s equation. Three isoflavone plasma concentrations (Genistein, daidzein, and equol) of 167 subjects among case-cohort subjects had been measured using time-resolved fluoroimmunoassay. Cubic spline curve for gastric cancer risk according to urinary sodium level was used to define optimal cut-off points of urinary sodium excretion concentration. Weighted Cox proportional hazard regression was used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs). Stratified analysis by isoflavone level was conducted to assess effect modification by isoflavone on the association between salt intake and gastric cancer. Results: Gastric cancer risk in the high salt intake group (urinary sodium excretion ≥6,000mg/day) was significantly increased (HR, 1.69; 95% CI, 0.99-2.90) compared to the reference group (urinary sodium excretion 4500-5,999mg/day). Magnitudes of gastric cancer risk by high salt intake were more strengthened in the group with low plasma isoflavone concentrations (One or no genistein, diadzein or equol levels over the median concentrations) (HR, 6.92; 95% CI, 1.80-26.56). Contrary to the low isoflavone group, no significant differences in gastric cancer risk according to salt intake levels were found in the group with high isoflavone concentration. Conclusions: High salt intake is associated with gastric cancer risk, but this association can be attenuated by high concentration of isoflavones. We suggest that sufficient intake of soybean products, the rich sources of isoflavone, may give protection against gastric cancer in the population with high salt intake. Citation Format: Jieun Jang, Yunji Hwang, Choonghyun Ahn, Kwang-Pil Ko, Aesun Shin, Keun-Young Yoo, Sue K. Park. Effect modification by isoflavones on the association between salt intake and gastric cancer risk: A case-cohort study within the Korean multi-center cancer cohort [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 2276. doi:10.1158/1538-7445.AM2017-2276
Abstract 5154: Enhancing tumor blood perfusion using orally active heparin to increase the distribution of anticancer therapeutics inside the tumor tissue
Authors: Jeong Uk Choi, Taslim A. Al-Hilal, Seung Woo Chung, Jisuk Yun, Hwajung Nam, Myungyun Lee, Jinha Hwang, Kyungjin Kim, Youngro Byun, Youngseok Cho, Seong Wook Lee
Journal: Cancer Research (2017)

Abstract Here, we suggest in the first time that the cancer associated thrombosis(CAT) might be one of the major factor which limit the tumor blood perfusion and drug distribution inside the tumor tissue by reducing the effective radius of blood vessels. In order to prevent CAT and achieve enhanced drug distribution, we developed orally active heparin to be combined with other anti-cancer therapies. We injected dye conjugated fibrinogen and chitosan nanoparticles to mice which were bearing highly thrombotic tumor to visualize CAT and nanoparticle distribution inside the tumor tissue. When CAT is prevented by heparin, we found that nanoparticle distribution and accumulation were significantly enhanced compared to the group not treated with heparin. This results signify that the CAT can limit the tumor perfusion and prevention of CAT can enhance the drug accumulation and distribution. We used highly thrombotic cancer models such as melanoma and pancreatic cancer to evaluate the therapeutic efficacy of the doxorubicin containing nanoparticle and the combination of oxaliplatin and gemcitabine when they are combined with heparin. We have found that when heparin is combined with each therapy, their tumor inhibition efficacy increased about 25% and also confirmed that this synergistic effect comes from enhanced drug distribution inside the tumor tissue by preventing the CAT using anticoagulant. These results were also supported by histological analysis. We have validated our hypothesis by showing that CAT can limit the tumor perfusion, which in turn brings reduced drug distribution inside the tumor tissue. We also confirmed that our oral heparin could enhance the tumor perfusion and the efficacy of anti-cancer therapeutics by preventing the CAT in the tumor tissue. Citation Format: Jeong Uk Choi, Taslim A. Al-Hilal, Seung Woo Chung, Jisuk Yun, Hwajung Nam, Myungyun Lee, Jinha Hwang, Kyungjin Kim, Youngro Byun, Youngseok Cho, Seong Wook Lee. Enhancing tumor blood perfusion using orally active heparin to increase the distribution of anticancer therapeutics inside the tumor tissue [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 5154. doi:10.1158/1538-7445.AM2017-5154