tbuckley/cabot-search huggingface dataset:
Abstract 2391: Microglia-stimulated glioblastoma cell invasion is dependent on the EGFR ligand amphiregulin
Authors: Bhavika Desai, Uttama Rath, Jeffrey E. Segall, Salvatore J. Coniglio
Journal: Cancer Research (2015)

Abstract Glioblastoma Multiforme (GBM) is one of the deadliest human cancers with a median survival rate of only one year following diagnosis. The highly infiltrative nature of GBM is one of the main reasons this cancer is so difficult to completely remove surgically. Therefore increasing our knowledge of the mechanism GBM cells use to invade normal brain is of critical importance in designing novel therapies. We recently showed that tumor associated microglia stimulate GBM cell invasion and this process is mediated by CSF-1R signaling. In this study, we seek to identify factors that are upregulated in microglia in a CSF-1R-dependent manner and ascertain whether they are involved in mediating invasion of GBM cells. We assayed cDNA and protein from microglia treated with conditioned media from the murine GBM cell line GL261, and discovered that the EGFR ligand amphiregulin (AREG) is strongly upregulated. This upregulation is blocked by addition of a pharmacological CSF-1R inhibitor. Using RNA interference, we show that microglia depleted of AREG can not promote invasion of GL261 cells into matrigel-coated invasion chambers as effectively. In addition, an AREG blocking antibody strongly attenuates the ability of THP1 macrophages to activate human GBM cell line U87 invasion. Furthermore, we have identified a signaling pathway which involves CSF-1R signaling through MAPK ERK to upregulate AREG expression in microglia and interfering with ERK using pharmacological inhibitors also prevents microglia-stimulated GL261 invasion. Interestingly, microglia that have been activated by GBM cells appear to require cell-cell contact in order to promote invasion. This data highlights AREG as a key factor in produced by tumor associated microglia in promoting glioblastoma invasion. Citation Format: Bhavika Desai, Uttama Rath, Jeffrey E. Segall, Salvatore J. Coniglio. Microglia-stimulated glioblastoma cell invasion is dependent on the EGFR ligand amphiregulin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2391. doi:10.1158/1538-7445.AM2015-2391
Abstract 1279: Expression of B7-H5 in human pancreatic caner
Authors: Yuwen Zhu, Joshua Byers, Alessandro Paniccia, Jeffrey Kaplan, Michelle Koenig, Richard Schulick, Barish Edil
Journal: Cancer Research (2015)

Abstract The B7-H5/CD28H pathway is the most recently identified costimulatory pathway of the B7 family. Here we investigated how the ligand B7-H5 is expressed in normal human pancreas tissues, as well as its expression changes in pancreas cancer. By immunohistochemical (IHC) staining of frozen specimens from patients undergoing pancreatic resection, we found that B7-H5 protein was constitutively expressed on normal ductal epithelium within the pancreas. Other cell types from normal pancreas, like acinar cells or islet cells, did not express B7-H5. In adenocarcinoma, B7-H5 staining was decreased or absent, though normal ducts adjacent to tumors were highly B7-H5-positive. No B7-H5 protein was found on other cancer types such as neuroendocrine tumors. Our study suggests that loss of the B7-H5 signal might contribute to immune evasion of pancreatic ductal adenocarcinoma. Citation Format: Yuwen Zhu, Joshua Byers, Alessandro Paniccia, Jeffrey Kaplan, Michelle Koenig, Richard Schulick, Barish Edil. Expression of B7-H5 in human pancreatic caner. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1279. doi:10.1158/1538-7445.AM2015-1279
Abstract 5101: The control of migration and invasion processes in colorectal adenocarcinoma is modulated by prion protein and its ligand STI1/HOP
Authors: Tonielli S. Lacerda, Marcos Vinicius S. Dias, Fernanda S. Giudice, Bianca Luise Teixeira, Vilma Regina Martins
Journal: Cancer Research (2015)

Abstract The colorectal cancer is one of the most common types of cancer in the world. Previous results from our group and others revealed the Cellular Prion Protein (PrPC) as a possible therapeutic target in glioblastomas and ovarian tumors. Its activity depends on the interaction with the secreted form of the Stress Inducible Protein 1 (STI1), also known as HSP70/90 Heat Shock Organizing Protein (HOP). In the present work, we aimed to understand the mechanism by which PrPC-STI1/HOP complex can influence the aggressiveness of colorectal tumor cell lines. Cell migration and invasion assays were performed using recombinant STI1/HOP as a chemical attractant in boyden chambers coated with matrigel. The results showed that when stimulated with recombinant STI1/HOP, cells exhibited higher migration and invasion potentials than non-stimulated cells or those that were stimulated with STI1/HOP deletion mutant for the PrPC binding domain (STI1Δ230-245). Moreover, migration and invasion mediated by STI1/HOP were blocked by a STI1/HOP peptide (230-245), which mimics STI1/HOP binding site to PrPC, as well as by a neutralizing anti-PrPC antibody. To confirm the importance of PrPC-STI1/HOP complex in tumor progression and metastasis we generated a stable PrPC-knockdown colorectal adenocarcinoma cell line (WIDr). These cells showed a decreased invasion upon recombinant STI1/HOP stimulus, suggesting an important role of PrPC-STI1/HOP complex in the invasion process. In addition, as ERK signaling pathway has been related to invasion, we evaluated the ERK1/2 phosphorylation pattern in WIDr wild-type cells and their PrPC knockdown (KD) counterpart. Cells where PrPC was impaired showed a reduction in ERK1/2 phosphorylation when compared to those expressing the former protein. Experiments are under way to evaluate if these lower ERK1/2 levels are associated with decreased migration in PrPC-KD cells. In conclusion, our findings pointed that the disruption of PrPC-STI1/HOP complex could be a therapeutic target in colorectal adenocarcinoma. Supported by São Paulo Research Foundation (FAPESP) Citation Format: Tonielli S. Lacerda, Marcos Vinicius S. Dias, Fernanda S. Giudice, Bianca Luise Teixeira, Vilma Regina Martins. The control of migration and invasion processes in colorectal adenocarcinoma is modulated by prion protein and its ligand STI1/HOP. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5101. doi:10.1158/1538-7445.AM2015-5101
Abstract A34: Oncogenic KRAS regulates pancreatic cancer cell signaling via stromal reciprocation
Authors: Christopher Tape, Stephanie Ling, Maria Dimitriadi, Kelly McMahon, Jonathan Worboys, Hui S. Leong, Ida Norrie, Crispin Miller, George Poulogiannis, Douglas Lauffenburger, Claus Jorgensen
Journal: Cancer Research (2016)

Abstract Pancreatic Ductal Adenocarcinoma is characterized by a reactive stroma, which modifies tumor progression and response to therapy. Oncogenic mutations regulate signaling both within tumor cells and adjacent stromal cells. However, defining whether oncogenes can regulate tumor cell signaling and phenotypic behavior via stromal cells is of importance to understand mechanisms of disease progression and response to therapy. Here we show that oncogenic KRAS (KRASG12D) regulates pancreatic cancer cell signaling via stromal stellate cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic stellate cells, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation, apoptosis, and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. Citation Format: Christopher Tape, Stephanie Ling, Maria Dimitriadi, Kelly McMahon, Jonathan Worboys, Hui S. Leong, Ida Norrie, Crispin Miller, George Poulogiannis, Douglas Lauffenburger, Claus Jorgensen.{Authors}. Oncogenic KRAS regulates pancreatic cancer cell signaling via stromal reciprocation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A34.
DAB2 interactive protein (DAB2IP) methylation in serum DNA of non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations.
Authors: J. Wei, J. L. Ramirez, M. Taron, J. J. Sanchez, S. Benlloch, R. Rosell, M. Botia, M. Perez-Cano, P. Mendez, M. Tierno, C. Queralt, I. de Aguirre, B. Sanchez, A. Martinez, C. Buges, J. Bosch, B. Massuti, C. Camps, J. M. Sanchez, T. Moran
Journal: Journal of Clinical Oncology (2011)

7593 Background: DAB2IP loss promotes primary tumor growth by activating Ras and drives metastasis through NFkB, serving as a signaling scaffold to coordinately regulate these pathways. DAB2IP is frequently methylated in lung cancer, and methylation in the m2a region is a key regulatory factor for DAB2IP expression in prostate cancer. We examined DAB2IP methylation in cell lines and in serum from erlotinib-treated NSCLC p with EGFR mutations. Methods: In human lung, breast and colorectal cancer cell lines, we analyzed DAB2IP promoter methylation in regions m2a and m2b by methylation-specific PCR (MSP) and bisulfite genomic sequencing. In circulating serum DNA from 152 erlotinib-treated NSCLC p with EGFR mutations, we analyzed methylation in the m2a and m2b promoter regions of DAB2IP by MSP. Methylation status was correlated with clinical outcome. Results: Methylation was detected in the m2a region of 42 (27.63%) p, and in the m2b region in 51 (33.55%) p. There were no major differences in clinical characteristics (age, gender, smoking history, EGFR mutation type, metastatic sites) between p with methylation in the m2a region and p with methylation in the m2b region. Overall progression-free survival (PFS) was 15 months (m), and median survival (MS) 28 m for all 152 p. For the 41 p with bone metastases (mets), PFS was 14 m for 30 p without methylation in the m2a region vs 8 m for 11 p with methylation in the m2a region (P=0.01), and MS was 23 m vs 10 m, respectively (P=0.19). For the 57 p with distant mets but no lung mets, PFS was 18 m for 36 p without methylation in the m2a region vs 10 m for 21 p with methylation in the m2a region (P=0.01), and MS was 24 m vs 16 m, respectively (P=0.03). No differences in either PFS or MS were observed according to the methylation status of the m2b region. Conclusions: Methylation in the m2a region of DAB2IP in serum DNA correlates with PFS and MS to erlotinib in NSCLC p with EGFR mutations with non-lung mets. Surveillance of DAB2IP methylation status in circulating DNA could be a useful tool to predict outcome to erlotinib in EGFR-mutated NSCLC p with non-lung mets.
Sex can affect participation, engagement, and adherence in trials
Authors: Alison Avenell, Clare Robertson, Fiona Stewart, Dwayne Boyers, Flora Douglas, Daryll Archibald, Edwin van Teijlingen, Pat Hoddinott, Charles Boachie
Journal: BMJ (2016)

We enjoyed Wallach and colleagues’ analysis of sex based subgroup differences in randomised controlled trials in the Cochrane Library.1 The authors found little evidence for clinically relevant sex-treatment interactions for outcomes.

Not apparent in their analysis are the social, psychological, and contextual factors that can influence men’s and women’s …
Proteomics-based characterization of potential biomarkers in tamoxifen resistance in breast cancer.
Authors: B. C. Sanchez, H. Johansson, J. Forshed, O. Stål, J. Lehtio, B. K. Linderholm
Journal: Journal of Clinical Oncology (2011)

628 Background: Despite the success of tamoxifen (tam) since its introduction there are patients with an estrogen (ER) and progesterone receptor-positive breast cancer (BC) that do not benefit from therapy. This represents a significant clinical problem acknowledging the need for reliable and useful predictive biomarkers. Techniques such as mass spectrometry (MS) enable simultaneous analyses of multiple proteins opening up possibilities in which to study the involvement of various pathways in the resistance mechanism. Our aim is to identify novel potential biomarkers predicting the effect of tam. Methods: Out of a consecutive patient cohort of primary ER positive BC stage I-II, subjected to adjuvant tam, 12 patients with early relapses within 2 years of tam treatment and 12 responsive (relapse-free > 7 years) were selected. MS was used to investigate proteomic changes between groups. Tumor homogenates were subjected to bottom up proteomics suggesting that quantification and identification occurred after sample digestion. Samples were iTRAQ-labelled and fractionated by immobilised pH gradient – isoelectric focusing prior to analysis with liquid chromatography electrospray ionization tandem MS. Proteome discoverer 1.1 with Mascot 2.2 was used for identification of proteins. Advanced uni- and multivariate biostatistical analyses were applied to identify significantly deregulated proteins. Results: 3,500 proteins were identified of which 32 were significantly deregulated in relapsing patients compared to responding ones. We proceeded by selecting 14 proteins based on expression ratio and relevant biological function. After an extensive literature research 4 proteins were chosen for final verification. Conclusions: Reliable differences in protein expression were observed between the tam-responsive and relapsing patients. We have successfully identified relevant deregulated proteins which were involved epithelial mesenchymal transition, metastasis, invasion, motility and metabolism. Further exploration of potential biomarkers will be verified in the complete original patient cohort and validated in an independent one.
Abstract 2246: Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells
Authors: Guillaume Vares, Sei Sai, Bing Wang, Akira Fujimori, Mitsuru Nenoi, Tetsuo Nakajima
Journal: Cancer Research (2015)

Abstract Among the four main subtypes of breast cancer, basal-like breast cancer (the predominant subtype of triple-negative breast cancer) is of particular concern, due to its high frequency, relative lack of effective therapies and poor prognosis. Ionizing radiation (for example as treatment for other cancers) and cumulative exposure to steroid hormones (as seen in postmenopausal women under hormone replacement therapy) are known risk factors for breast cancer. Because of their tumor-initiating properties, cancer stem cells (CSCs) were proposed to be responsible for relapse and metastasis. In MCF10A non-cancerous basal-like PR-negative cells, progesterone treatment and 1 Gy X-rays generated ALDH+ and CD44+/CD24- CSCs. Here, we report that progesterone activated the Pi3k/Akt pathway via membrane progesterone receptor (mPR). Inhibition of the Pi3k/Akt pathway counteracted the generation of CSCs by progesterone and irradiation. The stimulation of Pi3K/Akt by progesterone resulted in the inactivation of FOXO3 and a downregulation of miR-29 expression. Stabilization of miR-29 expression impeded the generation of CSCs, while its inhibition alone was sufficient to generate CSCs. This study provides a new mechanistic basis for progesterone and radiation-induced breast cancer risk. In addition, the elucidation of new pathways and miRNA regulations involved in CSC generation and maintenance may open the door to potential new strategies for basal cancer primary or adjuvant therapy, by blocking non-CSCs from replenishing the pool of CSCs and by targeting mechanisms responsible for CSC maintenance. Such CSC-focused therapies may be effective at preventing metastasis and relapse. Citation Format: Guillaume Vares, Sei Sai, Bing Wang, Akira Fujimori, Mitsuru Nenoi, Tetsuo Nakajima. Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2246. doi:10.1158/1538-7445.AM2015-2246
582. Role of MicroRNA Deregulation in Machado-Joseph Disease
Authors: Udaya Geetha Vijayakumar, Vítor Carmona, Clévio Nóbrega, Lígia Ferreira, Luís Pereira de Almeida
Journal: Molecular Therapy (2015)

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by an abnormal CAG expansion in the coding region of ATXN3/MJD1 gene. This confers a toxic gain-of-function to the ataxin-3 protein leading to neurodegeneration and severe motor impairments. There is no therapy to delay disease progression. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level. miRNAs have been reported to play a significant role in a variety of diseases, including neurodegenerative disorders. However, the profiles and regulation of miRNAs in MJD are not well understood. Therefore, the aims of this study were 1) to screen the microRNA levels in a MJD mouse model and 2) to investigate functional effects of reestablishing normal levels of the de-regulated miRNAs using the same MJD mouse model. For this purpose, we used a MJD striatal lentiviral mouse model that we previously described (Simões et al., 2012), by injecting mutant ataxin-3 in one hemisphere and wild type ataxin-3 (as an internal control) in the other hemisphere. Two weeks post-injection, miRNA expression was profiled by miRNA microarray analysis. Six miRNAs were found differentially expressed in MJD striatal samples, a result that was validated by qRT-PCR. We then used bioinformatic tools to predict the targets for the validated miRNAs and analyzed the respective levels. One candidate miR was up-regulated and the predicted target was down-regulated. To investigate whether reinstating the normal levels of the candidate miR would alleviate neuropathology, we then co-injected lentiviral vectors encoding an inhibitor of the candidate miR and mutant ataxin-3 in one hemisphere, and mutant ataxin-3 with miR negative inhibitor (as an internal control) in the other hemisphere. Five weeks post-injection we evaluated the neuropathological features and observed that in the hemisphere injected with the miR inhibitor there was a significant reduction of the loss of DARPP-32 neuronal marker and also a reduction of the mutant ataxin-3 aggregates as verified by western blot. Altogether our results provide new insights in the pathogenesis of MJD and identify a candidate miR that may be a promising target for MJD.
Abstract 4507: Intra-tumoral pharmacokinetic profiling for doxorubicin within solid tumor micromilieu using multicellular layers culture in-vitro
Authors: Ahmed M. Al-Abd, Fahad A. Al-Abbasi, Alaa Khedr, Salah G. Atteiah
Journal: Cancer Research (2015)

Abstract In contrast to plasma pharmacokinetics, intratumoral pharmacokinetics of DOX determines its spatial anti-tumoral activity. Three dimensional multicellular layers (MCL) model for solid tumors present optimum experimental platform for studying the intratumoral pharmacokinetics of DOX. This might imply new insights for understanding intratumoral pharmacokinetic parameters with realistic clinical implications. Herein, we are presenting simplified method for the spatial in-situ concentration assessment of DOX within the avascular simulating MCL solid tumor model of DLD-1 and HT-29 cell lines. DLD-1 and HT-29 formed viable well structured MCL model abundant in extracellular matrix component (fibronectin). DOX (100 μM) showed stronger anti-proliferative effect against MCL of DLD-1 compared to HT-29 MCL (38.8% and 27.9%, respectively). The differential potencies of DOX closely correlate to the intratumoral pharmacokinetics within MCL's of both cell lines. DOX penetrated faster and washed out slower through the MCL of DLD-1 compared to HT-29 MCL. Distribution of DOX within MCL of DLD-1 was more homogenous compared to HT-29 MCL. Tissue concentration of DOX within MCL of DLD-1 was significantly higher than HT-29 MCL's after 96 h exposure (0.7 and 0.4 μmole/gm tissue, respectively). Concentration of DOX within MCL of both cell lines exceeded the IC50 under monolayer conditions (2.3±0.6 μM and 0.6±0.1 μM, respectively). In addition, DOX was extensively metabolized to less active metabolites (doxorubicinol and doxorubicinone) during traversing the thickness of both MCL’s. In conclusion, Intratumoral pharmacokinetic barriers to DOX might be key determinant in drug resistance on the tissue level, despite cellular and molecular events. Citation Format: Ahmed M. Al-Abd, Fahad A. Al-Abbasi, Alaa Khedr, Salah G. Atteiah. Intra-tumoral pharmacokinetic profiling for doxorubicin within solid tumor micromilieu using multicellular layers culture in-vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4507. doi:10.1158/1538-7445.AM2015-4507
Two-Year Safety and Tolerability of Velaglucerase Alfa in Patients with Type 1 Gaucher Disease, Including Patients Switched From Imiglucerase: Phase III Trial HGT-GCB-039 and Extension,
Authors: A Mehta, H Ben Turkia, DE Gonzalez, M Kabra, EA Lukina, P Giraldo, I Kisinovsky, A Bavdekar, M-F Ben Dridi, N Gupta, PS Kishnani, EK Sureshkumar, N Barton, N Wang, E Crombez, K Bhirangi, A Zimran
Journal: Blood (2011)