bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3055: A permanent lung imaging window reveals, for the first time, the steps of extravasation, seeding and growth of early metastatic dissemination
Authors: Voiculescu Sonia E. , Wang Yarong , Oktay Maja , Condeelis John , Entenberg David 
Published: July 2017

Abstract
Metastatic disease is the major cause of cancer mortality and is responsible for over 1/2 million deaths each year in the U.S. alone. Of the three most common sites of metastasis observed clinically (bone, lung and liver), the most difficult to study using intravital microscopy is the lung; a delicate organ in perpetual motion. We have recently developed and validated an implantable, permanent, lung imaging window which allows high-resolution multiphoton imaging of the intact, breathing (without ventilation), murine lung over days to weeks of repeated imaging. This window does not use vacuum to immobilize the lung tissue thereby avoiding well know artifacts associated with vacuum lung windows. Using our new window, we have been able to visualize, with single cell resolution, the steps of metastasis in a clinically relevant, spontaneously-metastasizing murine breast cancer model. We present the first direct visualization of tumor cell arrival, extravasation, and progression to micro-metastases. Further, we have observed, for the first time, the activity of the tripartite structure called Tumor MicroEnvironment of Metastasis (TMEM) in metastatic lung lesions directly demonstrating the mechanism of dissemination from metastatic lung tumors. Using this approach to imaging live lung tissue serially, within a single animal, we are investigating the mechanisms underlying the fate of tumor cells arriving in the lung with the ultimate goal of directly identifying signals behind seeding and survival of metastatic tumor cells and their responses to interventions in real time.
Citation Format: Sonia E. Voiculescu, Yarong Wang, Maja Oktay, John Condeelis, David Entenberg. A permanent lung imaging window reveals, for the first time, the steps of extravasation, seeding and growth of early metastatic dissemination [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 3055. doi:10.1158/1538-7445.AM2017-3055
Abstract 3056: Genetic deletion of insulin-like growth factor binding protein-7 (IGFBP7) promotes hepatocellular carcinoma (HCC): a novel role of IGFBP7 in regulating antitumor immune surveillance
Authors: Akiel Maaged A. , Guo Chunqing , Li Xia , Rajasekaran Devaraja , Mendoza Rachel G. , Jariwala Nidhi H. , Robertson Chadia L. , Subler Mark A. , Windle Jolene J. , Fisher Paul B. , Sarkar Devanand 
Published: July 2017

Abstract
In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/-) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross-presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immunocompetent mice which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response.
Citation Format: Maaged A. Akiel, Chunqing Guo, Xia Li, Devaraja Rajasekaran, Rachel G. Mendoza, Nidhi H. Jariwala, Chadia L. Robertson, Mark A. Subler, Jolene J. Windle, Paul B. Fisher, Devanand Sarkar. Genetic deletion of insulin-like growth factor binding protein-7 (IGFBP7) promotes hepatocellular carcinoma (HCC): a novel role of IGFBP7 in regulating antitumor immune surveillance [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 3056. doi:10.1158/1538-7445.AM2017-3056
Abstract 3062: Metformin inhibits TGFβ-induced stromal ECM remodeling to impede invasion in ovarian cancer
Authors: Hart Peter C. , Sheikh Shermeen , Lengyel Ernst , Romero Iris 
Published: July 2017

Abstract
Recently, our group has elucidated that metformin, the commonly used medication for type 2 diabetes, has anti-ovarian cancer (OvCa) effects in preclinical models and use of the drug is associated with improved OvCa survival in retrospective epidemiological studies. While the cytotoxic effects of metformin in ovarian cancer cell lines is well demonstrated, the impact of metformin on tumor-stromal interactions in the tumor microenvironment is not well defined. Currently, our work has focused on the impact of metformin on the tumor microenvironment and cancer cell behavior in physiologic models of tumor metastasis. Using a 3D organotypic model, we demonstrate that OvCa cell invasion is inhibited by metformin. In evaluating the molecular mechanism mediating this effect we show that OvCa cells co-cultured with stromal cells or stimulated with TGFβ1 upregulate the production of the extracellular matrix (ECM) proteins fibronectin and collagen 1 and that this effect is attenuated by metformin. Interestingly, metformin’s inhibition of ECM production was not dependent on AMP-activated kinase (AMPK), a common metformin target. To expand on this finding we performed label-free shotgun proteomics and identified collagens, fibronectin and TGFBR2 to be among the proteins most highly repressed in response to metformin exposure in OvCa cells. Finally, we identified that this repression of ECM remodeling by metformin was associated with an overall reduction in TGFBR2 expression and consequent SMAD/STAT3 activity. Taken together, our data indicate that metformin may have novel targets in the tumor microenvironment where it targets pro-tumorigenic effects of the stromal compartment by repressing TGFβ-dependent stromal cell ECM secretion, thereby inhibiting ovarian cancer invasion and metastasis.
Citation Format: Peter C. Hart, Shermeen Sheikh, Ernst Lengyel, Iris Romero. Metformin inhibits TGFβ-induced stromal ECM remodeling to impede invasion in ovarian 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 3062. doi:10.1158/1538-7445.AM2017-3062
Abstract 3063: Predicting efficacy of c-Met targeting therapy in autocrine and paracrine tumor cell lines
Authors: Hughes Veronica S. , Siemann Dietmar W. 
Published: July 2017

Abstract
Tumor cells frequently harbor abnormalities in signaling pathways, leading to increased migration, invasion, survival, angiogenesis, and proliferation. C-Met is one such commonly aberrant pathway. Because of its effects on tumor cells, c-Met has been a target of interest for anti-metastatic therapies. Clinical trials of c-Met inhibition select patients based on total Met expression, or amplification of the Met gene. However, c-Met inhibitors target the activated pathway. We therefore predict that phospho-Met will be a better marker for patient sensitivity to, and hence selection for, c-Met inhibitor trials. C-Met is activated by the endogenous ligand Hepatocyte Growth Factor (HGF). In order to mimic the paracrine signaling during in vitro experiments, many studies add exogenous HGF at concentrations of 25-50 ng/mL. However, these concentrations may not be representative of in vivo conditions. HGF serum levels of healthy humans is 0.4 ng/mL. While HGF levels do rise in cancer patients, it is unusual to see serum levels higher than 1 ng/mL. Conditioned media from several cell lines (MDA-MB-231, PC-3, DU145, LNCaP, OS156, OS521, U87, U118, RKO, KHT, SCC7, and RIF) was collected to analyze for secretion of HGF in conditioned media. These cells were then examined for basal phosphorylation of Met. The cell lines that secreted HGF also had higher levels of phospho-Met in comparison to non-HGF-secreting cell lines. Importantly, levels of total Met did not predict for levels of phospho-Met. In migration and invasion assays, the HGF-secreting cell line KHT was found to be sensitive to the c-Met inhibitor BMS-777607.The non-HGF-secreting cell line DU145 only became sensitive to the inhibitor when high, non-physiologic exogenous levels of HGF (25-50 ng/mL) were added.These results suggest that autocrine activation of the c-Met pathway may be a factor in predicting sensitivity to c-Met inhibition. This may indicate the existence of a subset of patients most likely respond to c-Met inhibition therapy. Furthermore, consideration of exogenous HGF concentration should be considered when conducting preclinical trials of c-Met inhibitors, as addition of exogenous HGF may change the apparent efficacy of the inhibitor.
Citation Format: Veronica S. Hughes, Dietmar W. Siemann. Predicting efficacy of c-Met targeting therapy in autocrine and paracrine tumor cell lines [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 3063. doi:10.1158/1538-7445.AM2017-3063
Abstract 3066: Inhibition of hsp90 by auy922 preferentially kills mutant KRAS colon cancer cells by activating Bim through ER stress
Authors: Wang Chun Yan , Guo Su Tang , Wang Jia Yu , Yan Xu Guang , Farrelly Margaret , Zhang Yuan Yuan , Liu Fen , Yari Hamed , La Ting , Lei Fu Xi , Jin Lei , Jiang Chen Chen , Zhang Xu Dong 
Published: July 2017

Abstract
Colon cancer is one of the most common and deadly malignancies (1). Despite recent advances in early diagnosis and the development of molecularly targeted therapy, the overall survival of patients with metastatic colon cancers remains disappointing (1). This is often associated with resistance of colon cancer cells to systemic therapies resulting from oncogenic mutations of KRAS that drive activation of multiple downstream signalling pathways important for cell survival and proliferation. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the heat shock protein 90 (HSP90) inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with the comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with activating mutations of KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3 only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. In addition, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and that agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy.
Citation Format: Chun Yan Wang, Su Tang Guo, Jia Yu Wang, Xu Guang Yan, Margaret Farrelly, Yuan Yuan Zhang, Fen Liu, Hamed Yari, Ting La, Fu Xi Lei, Lei Jin, Chen Chen Jiang, Xu Dong Zhang. Inhibition of hsp90 by auy922 preferentially kills mutant KRAS colon cancer cells by activating Bim through ER stress [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 3066. doi:10.1158/1538-7445.AM2017-3066
Abstract 3071: Exploring the molecular mechanism underlying SETD2-PI3Kβ synthetic-lethal interaction in renal cell carcinoma (RCC)
Authors: Terzo Esteban , Chiang Jeanne , Rathmell W. Kimryn 
Published: July 2017

Abstract
Epigenetic regulators are emerging as major drivers of renal cell carcinoma (RCC). SETD2, a tumor suppressor commonly mutated in RCC, is the sole enzyme responsible for tri-methylating histone H3 on lysine 36 (H3K36me3) of actively transcribed genes. We recently discovered that SETD2 also trimethylates the non-histone target α-tubulin on lysine 40 (α-TubK40Me3) of mitotic microtubules. We have demonstrated that mutations altering SETD2’s ability to trimethylate H3K36 and α-TubK40 are associated with genomic instability in cancer progression. We hypothesized that defective SETD2 methylating activity gives rise to deleterious cell signaling cascades that promote the tumorigenic features of SETD2 loss. Preliminary data show that RCC-derived 786-0 cells that are deleted for SETD2 (SETD2-KO) or harbor pathogenic mutations are more sensitive to treatment with the PI3Kβ-specific inhibitor TGX-221 than their wild type counterparts. Phosphatidylinositol 3kinases (PI3Ks) are a family of lipid kinases that coordinate signals from growth factors, cytokines and other environmental cues, translating them into intracellular signals controlling diverse signaling pathways. Several members of the PI3K/AKT signaling pathway, including the PI3K α and β isoforms, are frequently mutated in a variety of cancers, making this pathway a prime drug target for anti-cancer therapy. These pathways control numerous biological processes, such as cell proliferation, growth, and motility. Examination of structurally variant SETD2 mutants suggests that the loss of SETD2 methylating activity mediates this interaction, and future studies will examine the functional consequences of inhibiting this pathway. In summary, these data suggest a synthetic-lethal type of interaction between SETD2 loss (and specifically loss of methylating activity) and an aberrant PI3K/AKT pathway.
Citation Format: Esteban Terzo, Jeanne Chiang, W. Kimryn Rathmell. Exploring the molecular mechanism underlying SETD2-PI3Kβ synthetic-lethal interaction in renal cell carcinoma (RCC) [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 3071. doi:10.1158/1538-7445.AM2017-3071
Abstract 308: The PP2A-B56 phosphatase opposes cyclin E autocatalytic degradation via site-specific dephosphorylation
Authors: Davis Ryan J. , Swanger Jherek , Clurman Bruce E. 
Published: July 2017

Abstract
Cyclin E, in conjunction with its catalytic partner cyclin-dependent kinase 2 (CDK2), regulates cell cycle progression as cells exit quiescence and enter S-phase. Multiple mechanisms control cyclin E-CDK2 activity during the cell cycle, including phosphorylation-dependent cyclin E ubiquitylation by the SCFFbw7 ubiquitin ligase. Serine 384 (S384) is the critical cyclin E phosphorylation site that stimulates Fbw7 binding and subsequent cyclin E degradation. Because S384 is autophosphorylated by CDK2, cyclin E therefore instigates its own degradation in an autocatalytic manner. This presents a paradox as to how cyclin E-CDK2 is able to phosphorylate its numerous substrates prior to cyclin E autophosphorylation-catalyzed degradation. Here we find that the PP2A-B56 phosphatase specifically dephosphorylates cyclin E at S384, thereby uncoupling cyclin E degradation from cyclin E-CDK2 activity. Furthermore, the rate of S384 dephosphorylation is high in interphase and low in mitosis, allowing PP2A-B56 to oppose autocatalytic cyclin E degradation and maintain cyclin E-CDK2 activity at the G1/S transition.
Citation Format: Ryan J. Davis, Jherek Swanger, Bruce E. Clurman. The PP2A-B56 phosphatase opposes cyclin E autocatalytic degradation via site-specific dephosphorylation [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 308. doi:10.1158/1538-7445.AM2017-308
Abstract 3115: Characterization of CDCA1 protein as a novel prognostic biomarker and therapeutic target for oral cancer
Authors: Phung Thang Manh , Takano Atsushi , Yoshitake Yoshihiro , Shinohara Masanori , Murakami Yoshinori , Daigo Yataro 
Published: July 2017

Abstract
Oral cavity carcinoma (OCC) is one of the most common causes of cancer-related death worldwide. Current therapies for OCC still show poor clinical outcome with five-year survival rate of less than 63%. Therefore, next generation biomarkers and therapeutic strategies for OCC are eagerly awaited. We selected genes that were specifically overexpressed in the majority of OCC using our gene expression profile database, and identified cell division cycle associated 1 (CDCA1) that appeared to encode nuclear protein as a candidate. Immunohistochemical analysis using tissue microarray covering 99 OCC tissues detected that CDCA1 protein was expressed in 67 cases of 99 OCC tissues (68%), but not in normal oral epithelia. In addition, high levels of CDCA1 protein expression was significantly associated with poor prognosis for OCC patients (P = 0.0244 by log-rank test). Furthermore, knockdown of CDCA1 expression by siRNAs significantly inhibited the growth of tumor cells. Moreover, flow cytometric analysis, multiple apoptosis assays, and live cell imaging experiment revealed that CDCA1 could be important for the growth and survival of OCC cells, probably through the regulation of mitotic prophase and/or apoptosis. Our findings suggest that CDCA1 is likely to be a novel prognostic biomarker and a therapeutic target for OCC patients.
Citation Format: Thang Manh Phung, Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yoshinori Murakami, Yataro Daigo. Characterization of CDCA1 protein as a novel prognostic biomarker and therapeutic target for oral 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 3115. doi:10.1158/1538-7445.AM2017-3115
Abstract 3118: Histological subtypes correlate with distinct genetic abnormalities in defining therapeutic targets in medulloblastoma
Authors: Gelnick Samuel , Amin Anubhav G. , Gordon Molly , Medeiros Raphael Salles Scortegagna de , Zanon Nelci , Murali Raj , Jhanwar-Uniyal Meena 
Published: July 2017

Abstract
Medulloblastoma (MB) is the most common primary pediatric malignant brain tumor. Genetic classification and distinct histologic subtypes defines MB into 4 groups: classic (WNT), sonic hedgehog (Shh), group 3 and group 4. In addition, recent studies have provided evidence that p53 abnormalities is seen in various sub-groups of MB and that p53-mutated SHH MBs commonly harbor genetic anomalies including MYCN and GLI2 amplifications, which confers drug resistance. Here, we test the hypothesis that specific immunohistological markers, their correlation with the amplification of the oncogene MYC, and abnormalities in tumor suppressor gene p53, may define their metastatic potential.
Materials and Methods: Immunohistological analysis of MB tumors (n=41) was evaluated for the expression of glioma transcription factor 1 (GLI-1), Grb2-associated binding protein 1 (GAB-1), natriuretic peptide receptor (NPR), voltage-gated potassium channel (KV1) and mutant p53. FISH analysis was performed to determine MYC amplification or iso- P53. p53-mutant MB cell line was used to investigate the signaling pathway leading to proliferation, migration, and drug resistance using HDAC (LBH-589) and PI3K/mTOR (BKM-120/rapamycin) inhibitors.
Results: we showed that: 1) GAB-1 was highly expressed in the Shh group (82%) and KV1 expression was evenly distributed in all subtypes; 2) No obvious correlation with expression of GLI-1, GAB-1, NPR, or KV1 with metastasis was seen; 3) Analysis of loss of p53 and overexpression of MYC varied in each subtype; 4) Combined Treatment with LBH-589 and BKM-120 reduced cell proliferation, migration and S-phase entry, however, MB cells were resistant to BKM -120 treatments, while LBH-589 caused massive apoptosis; 5) Tumor formation was suppressed by BKM-120 given with mTOR inhibitors.
Conclusion: the result of this study suggests that expression of GLI-1, GAB-1, NPR, KV1 and p53 was important in defining the subgroups of MB, although their metastatic potential remains to be understood. MB cells shows reduced cell proliferation, cell cycle and migration, when treated with HDAC inhibitor LBH-589, however these cells display complete drug resistance to PI3K inhibitors.
Citation Format: Samuel Gelnick, Anubhav G. Amin, Molly Gordon, Raphael Salles Scortegagna de Medeiros, Nelci Zanon, Raj Murali, Meena Jhanwar-Uniyal. Histological subtypes correlate with distinct genetic abnormalities in defining therapeutic targets in medulloblastoma [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 3118. doi:10.1158/1538-7445.AM2017-3118