bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C282: The carcinogen cadmium is a HIF1A stabilizer that reduces HIF1 activity through cytosolic sequestration of HIF1A within K63-linked ubiquitinated aggregates.
Authors: Chargui Abderrahman , Belaid Amine , Vouret Valérie , Tauc Michel , Pouysségur Jacques , El May Michèle Véronique , Hofman Paul , Poujeol Philippe , Mograbi Baharia 
Published: August 2014

Abstract
Hypoxia-inducible factor-1 (HIF1) is a master transcription factor that orchestrates the adaptation of tumor cells to hypoxia by activating the expression of a broad range of genes promoting neoangiogenesis, tumor growth, glycolysis, metastasis, and resistance to treatments. Accumulating evidence now suggests that this adaptation depends on the stabilization or the increased synthesis of the HIF1A subunit. To have a better understanding of HIF1A regulation, we focused our attention on the environmental carcinogen cadmium (Cd). Our data now challenge these hypotheses and reveal unique and opposing activities of Cd on HIF1A expression and activity. Instead of a mere action on synthesis, Cd increases by itself the stability of HIF1A protein under normoxia; independently of proteasome impairment, oxidative damage or endoplasmic reticulum stress. However, little if any HIF1A is able to translocate to the nucleus of Cd-treated cells where it activates barely HIF1 transcriptional function. Consistently, Cd dominantly inhibited hypoxia-induced HIF1 activity. Interestingly, HIF1A stabilization and inhibition of activity coincided with its association with cytosolic K63-linked ubiquitinated aggregates. We therefore propose that Cd would stabilize HIF1A but the exaggerated K63 ubiquitination would foster aggregation of HIF1A with ubiquitinated proteins, thus precluding HIF1A from interacting with its downstream nuclear targets. The unique stabilization and sequestration of HIF1A we highlighted with cadmium unravels a novel regulatory mechanism of HIF1 activity.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C282.
Citation Format: Abderrahman Chargui, Amine Belaid, Valérie Vouret, Michel Tauc, Jacques Pouysségur, Michèle Véronique El May, Paul Hofman, Philippe Poujeol, Baharia Mograbi. The carcinogen cadmium is a HIF1A stabilizer that reduces HIF1 activity through cytosolic sequestration of HIF1A within K63-linked ubiquitinated aggregates. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C282.
Abstract C285: TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiation therapy.
Authors: Gao Chan 
Published: August 2014

Abstract
Recent studies suggested that cancer radiotherapy is potentially immunogenic. However, it is unclear why such effects rarely prevent tumor recurrence. Here, we uncover a novel Toll-like Receptor 9 (TLR9)-dependent mechanism initiating tumor regrowth after local radiotherapy. Systemic inhibition of TLR9, but not TLR4, delayed the recurrence of B16 melanoma, MB49 bladder, and CT26 colon cancers after localized, high dose tumor irradiation. We demonstrate that soluble factors present in the microenvironment of regressing tumors trigger TLR9 signaling in freshly recruited myeloid cells within four days after radiotherapy. The tumorigenic effects of TLR9 depended on rapid upregulation of IL-6 expression, which in turn resulted in downstream activation of Jak/STAT3 signaling in myeloid cells. By comparing global gene expression in wild-type, Tlr9-, or Stat3-deficient myeloid cells derived from irradiated tumors, we identified a unique set of TLR9/STAT3-regulated genes involved in tumor-promoting inflammation and revascularization. To assess whether blocking STAT3 can correct the aberrant TLR9 signaling, we used mice with a myeloid cell-specific Stat3 gene ablation or we treated mice using CpG-Stat3 siRNA to target TLR9-positive cells. Both approaches confirmed that targeting STAT3 in myeloid cells abrogates TLR9-mediated cancer recurrence after radiation therapy. Our results suggest that combining localized tumor irradiation with myeloid cell-specific inhibition of TLR9/STAT3 signaling can generate new strategies for the elimination of radiation resistant cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C285.
Citation Format: Chan Gao. TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C285.
Abstract C289: The kinin B1 receptor enhances the host protective response against murine melanoma aggressiveness.
Authors: Maria Andrea G. , Dillenburg-Pilla Patrícia , dos Reis Rosana Inácio , Medeiros Elaine Floriano , Tefé-Silva Cristiane , Ramos Simone Gusmão , Pesquero João Bosco , Costa-Neto Claudio Miguel 
Published: August 2014

Abstract
The incidence of malignant melanoma has significantly increased in the last few decades and advanced cases of this disease are still resistant to all types of therapies and represent a therapeutic challenge. Tumor development and growth depend on alterations that lead to an unlimited replicative potential, evasion of apoptosis and escape from immune response and also, on a permissive microenvironment. Chronic and persistent inflammation may also contribute to cancer development, and the relationship between the kinin B1 receptor and inflammation is well established. Furthermore, previous studies have shown that the kinin B1 receptor attenuates primary melanoma and metastasis. In this study, we show the role of the B1 receptor in the host tumor microenvironment during melanoma progression. To investigate this phenomenon, we inoculated B16F10 cells in wild type and B1 receptor-knockout mice, tumors were removed and several approaches were evaluated such as proliferation and cell survival pathways by western blotting, vascularization and mitosis by histology and cytokines expression levels by real time PCR. Our results show that the presence of the B1 receptor in the microenvironment did not represent a significant factor to modulate tumor size and time of appearance. Nevertheless, molecular analysis revealed that the lack of the B1 receptor resulted in development of tumors with more aggressive features. The melanomas that developed in the B1 receptor-knockout mice had the same vascularization as melanomas developed in the wild type animals but presented higher number of cells in mitosis, and the proliferative signaling pathways in the B1 receptor-knockout tumors were more strongly activated. Likewise, these tumors had lower levels of p38 and JNK activation, and higher levels of IL-10. Additionally, the tumors that developed in the B1 receptor-knockout mice were able to disrupt the skin near the tumor area. Taken together, our results suggest that the B1 receptor has an important role in supporting the host immune response against melanoma aggressiveness.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C289.
Citation Format: Andrea G. Maria, Patrícia Dillenburg-Pilla, Rosana Inácio dos Reis, Elaine Floriano Medeiros, Cristiane Tefé-Silva, Simone Gusmão Ramos, João Bosco Pesquero, Claudio Miguel Costa-Neto. The kinin B1 receptor enhances the host protective response against murine melanoma aggressiveness. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C289.
Abstract C294: Involvement of iNOS/NO and ROS in a reciprocal interaction of glioma and microglia cells via TNF-α and MCP-1 production.
Authors: Chen Yen-chou 
Published: August 2014

Abstract
The tumor microenvironment plays a critical role in glioblastoma invasion and progression, and microglia is one of the most abundant immune cells in the tumor. Using transwell co-culture methods with glioma cells (U87 and C6) and microglia cells BV-2, increased migration of glioma cells U87 and C6 by microglia BV2 cells or NO donor sodium nitro prusside (SNP) accompanied by increased NO production was observed, and BV2 co-culture-induced migration of U87 and C6 was blocked by adding a nitric oxide synthase (NOS) inhibitor N-nitro L-arginine methyl ester (NAME). The conditioned mediums (CM) derived from both glioma cells U87 and C6 (U87-CM and C6-CM) were prepared, CMs from glioma cells significantly induced iNOS protein and NO production cells in according with an occurrence of activated macrophages and without alternations in cell viability and cell cycle progression in microglia BV2. ERK inhibitor U0126 and JNK inhibitor SP600125 suppressed U87-CM and C6-CM-induced iNOS/NO production with respectively blocking phosphorylated ERK (pERK) and JNK (pJNK) protein expression stimulated by U87-CM and C6-CM. A significant increase in intracellular peroxide by U87-CM and C6-CM was detected via DCHF-DA assay, and vitamin C (Vit C) and N-acetyl cysteine (NAC)-reduced intracellular peroxide levels with inhibition of iNOS/NO production and pERK/pJNK protein stimulated by U87-CM and C6-CM were identified in BV-2 cells. Contribution of ROS, pERK, and pJNK to the migration of glioma cells was further demonstrated in the transwell co-culture system of glioma U87 and C6 with microglia BV-2 cells. Furthermore, TNF-α, MCP-1, CSF-1, and TGF-β were applied, and TNF-α and MCP-1 induced iNOS protein expression in time and concentration-dependent manners, and expression of TNF-α and MCP-1 mRNA in U87 and C6 cells were detected by RT-PCR. Neutralization of TNF-α or MCP-1 in U87-CM and C6-CM using TNF-α or MCP-1 antibody inhibited iNOS protein expression, and increased intracellular peroxide by TNF-α or MCP-1 was identified in BV2 cells. The reciprocal activation of glioma cells and microglia via ROS-dependent iNOS/NO elevation at least in part mediated by TNF-α and MCP-1 is elucidated.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C294.
Citation Format: Yen-chou Chen. Involvement of iNOS/NO and ROS in a reciprocal interaction of glioma and microglia cells via TNF-α and MCP-1 production. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C294.
Abstract C3: Tumor-derived soluble uPAR regulates tumor angiogenesis via PTEN.
Authors: Prager Gerald W. , Unseld Matthias , Poettler Marina , Zielinski Christoph 
Published: August 2014

Abstract
The urokinase receptor uPAR (CD87), a GPI-anchored protein, is frequently over-expressed in tumor cells. uPAR provokes numerous cellular functions by focusing proteolytic activity on the cell surface, but also by inducing intracellular signal transduction via transmembrane interaction partners, thus inducing cell migration and invasion as well as cell survival. Soluble tumor-derived uPAR has recently been described to activate endothelial cells and was suggested to promote angiogenesis. Consistently, high uPAR expression in tumor cells or high serum levels of circulating uPAR predict worse prognosis of breast, lung or colorectal cancer patients. In this study, we found that tumor-derived soluble uPAR is a key regulator of PTEN expression in endothelial cells. HEK cells deficient in endogenous uPAR or uPAR deficient endothelial cells derived from uPAR -/- mice had high PTEN mRNA as well as protein levels, while reconstitution of endogenous as well as addition of soluble exogenous uPAR decreased PTEN levels. uPAR, thereby, led to an integrin-dependent activation of the NFkB pathway, a known transcription pathway inhibitor of PTEN. As a consequence of PTEN downregulation, the downstream PKB/Akt signalling pathway became activated, which led to an enhanced migratory as well as cell survival activity in endothelial cells. Cross-breeding of uPAR -/- mice with endothelial cell-specific PTEN +/- mice, thereby led to a rescue of the high migratory phenotype of PTEN heterozygous endothelial cells in vitro and angiogenesis formation in a directed in vivo angiogenesis assay (DIVAA). From our date we conclude that tumor-derived uPAR is a major regulator of PTEN expression in endothelial cells, which leads to the induction of the PI3K/Akt-pathway and an enhanced angiogenic phenotype.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C3.
Citation Format: Gerald W. Prager, Matthias Unseld, Marina Poettler, Christoph Zielinski. Tumor-derived soluble uPAR regulates tumor angiogenesis via PTEN. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C3.
Abstract C38: Comparative evaluation of three real-time PCR assays for the detection of PIK3CA somatic mutations in formalin-fixed paraffin embedded breast carcinomas.
Authors: Harlé Alexandre , Lion Maëva , Rouyer Marie , Lozano Nicola , Merlin Jean-Louis 
Published: August 2014

Abstract
Background: Mutations of the PIK3CA gene encoding for the p110α catalytic subunit of Phosphatidylinositol 3-kinases (PI3K) are found in approximately 25% of breast carcinomas. Most of PIK3CA mutations are reported as activators of the PI3K/AKT/mTOR pathway and lead to resistance to anti-HER2 therapies, and have an interest in molecular diagnosis for anti-mTOR and/or anti-PI3K therapies. Highly sensitive methods are required to detect PIK3CA mutations in paraffin-embedded tumor tissues.
Methods: Forty-seven formalin-fixed paraffin embedded breast carcinomas tissues samples were assessed using two allele specific assays (Cobas® PIK3CA Mutation Test and PCR ARMS Scorpions®) and one non-specific real-time high resolution melting PCR assay (HRM) after macrodissection and DNA extraction. Cobas® allow the detection of 17 mutations on exons 1, 4, 7, 9 and 20 of PIK3CA, ARMS focuses on the detection on the four common hotspots (E542K, E545K/D, H1047R and H1047L) representing 90% of PIK3CA mutations and HRM allows the detection of all mutations located on the whole exons 9 and 20 of PIK3CA. Kappa statistics were used to compare the three assays.
Results: Among the 47 samples, 18 (38.3%) were found to bear a PIK3CA mutation with Cobas®, 13 (27.7%) with ARMS and 19 (40.4%) with HRM. One sample was found to bear 3 mutations of PIK3CA (E542K, H1047X and H1049R). Calculated kappa were 0.893 (p&lt;1.10-9) between Cobas® and HRM and 0.659 (p&lt;1.10-9) between Cobas® and ARMS. Because the ARMS assay only focused on the 4 most common PIK3CA mutations, more than 10% of the samples were identified as false negative wild-type tumors although they had a mutation of PIK3CA as identified with Cobas® and HRM assays.
Conclusion: Cobas® and HRM assays allowed to detect more extensively PIK3CA mutations than ARMS assay. ARMS assay only focusing on the 4 hotspots PIK3CA mutations seems to be inadequate with routine use since generating false negative PIK3CA wild-type results. Cobas® and HRM assays are significantly comparable for the detection of PIK3CA mutations, but Cobas® enables the characterization of the mutation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C38.
Citation Format: Alexandre Harlé, Maëva Lion, Marie Rouyer, Nicola Lozano, Jean-Louis Merlin. Comparative evaluation of three real-time PCR assays for the detection of PIK3CA somatic mutations in formalin-fixed paraffin embedded breast carcinomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C38.
Abstract C41: BRAFV600 serum/plasma analysis: Predictive value of survival in melanoma treated with BRAF inhibitors.
Authors: Gonzalez Cao Maria , Martin Algarra Salvador , Muñoz Eva , Mayo de las Casas Clara , Manzano Jose Luis , Cortes Javier , Molina-Vila Miguel Angel , Berros Jose Pablo , De Mattos-Arruda Leticia , Sanmamed Miguel , Gonzalez Alvaro , Alvarez Carlos , Karachaliou Niki , Rosell Rafael 
Published: August 2014

Abstract
Background: BRAF mutation is present in 50% of metastatic melanoma patients. Treatment with BRAF inhibitors improves survival of BRAF mutant melanoma patients, with a median progression free survival time of 6 months. Twenty percent of patients are refractory to BRAF inhibitors, and others have early resistance development. Pretreatment analysis of BRAFV600 mutation in cell free DNA from serum or plasma could help to select patients for BRAF inhibitor treatments. We have investigated the sensitivity of the assay and its predictive value. Methods: Analysis of BRAFV600 mutation was performed in cell free DNA (cf DNA) from serum and plasma of 22 metastatic melanoma patients before starting a BRAF inhibitor treatment. Results: Six patients were women, median age was 62 years old (58-81). Four patients (18%) had complete response to treatment. Eleven patients (50%) had partial response to treatment. Two patients (9%) had progression disease as their best response. Median progression free survival time (PFS) for patients with complete response, partial response, stable disease and progression disease were: not reached, 4.6 months, 3 months and one month, respectively (p&lt;0.00001). Twelve patients (54.5%) had BRAF positive analysis pretreatment in serum/plasma. From BRAF serum/plasma positive patients 1 had CR (8%) and 7 PR (58%). From BRAF serum/plasma negative patients: 3 (30%) CR and 4 (40%) PR. Median PFS for patients treated with BRAF inhibitors was 3.5 months for BRAF serum/plasma positive patients and 13.57 months for BRAF serum/plasma negative patients (p=0.026) Conclusion: BRAFV600 serum/plasma analysis is a good predictor of survival for patients treated with BRAF inhibitors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C41.
Citation Format: Maria Gonzalez Cao, Salvador Martin Algarra, Eva Muñoz, Clara Mayo de las Casas, Jose Luis Manzano, Javier Cortes, Miguel Angel Molina-Vila, Jose Pablo Berros, Leticia De Mattos-Arruda, Miguel Sanmamed, Alvaro Gonzalez, Carlos Alvarez, Niki Karachaliou, Rafael Rosell. BRAFV600 serum/plasma analysis: Predictive value of survival in melanoma treated with BRAF inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C41.
Abstract C50: Down-regulation of Bcl2 sensitizes radiation resistance prostate cancer cells to ionizing radiation.
Authors: Wang Tao , Carraway Robert E. , Briggs Joshua , Chen Huazhen , FitzGerald Thomas J. 
Published: August 2014

Abstract
Radiation therapy (RT) is an important treatment for primary prostate cancer (PCa). However, intermediate and high risk patients can relapse and recurrent disease can be resistant to RT. Bcl2 is one of the critical regulators of apoptotic cell death. Previously, we selected from the DU145 cell line (DU) a subset of cells (DUIR) that survive fractionated high dose ionizing radiation (IR) in vitro. In the current work, we have identified Bcl2 as an important regulator that determines IR resistance and IR-induced aggressiveness in PrCa cells. DUIR has undergone epithelial-mesenchymal transition (EMT) as defined by reduced E-cadherin and enhanced vimentin expression. DUIR cells display higher levels of neurotensin receptor 1 (NTR1), neuron specific enolase (NSE) and chromogranin B, resembling a neuroendocrine (NE) phenotype. DUIR survives better than DU when exposed to IR (6-10 Gy) or to zinc-directed toxins, and DUIR grows faster in response graded levels of serum or NT. NTR1 antagonist (SR48692) blocks the response to NT. NT stimulation reduces apoptosis while SR486923 enhances apoptosis in DUIR cells exposed to IR. The expression level of Bcl2 is dramatically higher in DUIR than in DU. To assess the role of Bcl2 in the ability of cells to survive IR, we generated stable cell lines using lentivirus caring Bcl2 specific shRNA. Down-regulation of Bcl2 sensitized the cells to IR, as shown by decreased proliferation, decreased clonogenicity, increased apoptosis (cleaved PARP and caspase 3/7 activity), and increased DNA breakage (γ-H2AX foci), as compared to control cells. Our study indicates that PCa cells that survive high dose IR display an aggressive phenotype characterized by NE and EMT features with resistance to IR or drug induced cell death. The up-regulation of Bcl2 plays an important role in cell survival following IR. These findings define a mechanism of cellular resistance to IR therapy and they suggest that strategies aimed to limit the effects of Bcl2 could be beneficial.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C50.
Citation Format: Tao Wang, Robert E. Carraway, Joshua Briggs, Huazhen Chen, Thomas J. FitzGerald. Down-regulation of Bcl2 sensitizes radiation resistance prostate cancer cells to ionizing radiation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C50.
Abstract C51: eIF2alpha phosphorylation determines cell susceptibility to oxidative stress via Akt activation.
Authors: Koromilas Antonis E. , Kamindla Rajesh , Papadakis Andreas I. , Kazimierczak Urszula , Peidis Philippos , Wang Shuo , Tenkerian Clara , Krishnamoorthy Jothi-Latha , Hatzoglou Maria , Haj Fawaz G. , Ferbeyre Gerardo , Kaufman Randal J. 
Published: August 2014

Abstract
Eukaryotic cells respond to various forms of stress by blocking mRNA translation initiation via the phosphorylation of the alpha (α) subunit of eIF2 at serine 51 (S51) (eIF2αP). Herein, we demonstrate that increased eIF2αP facilitates the adaptation of cells to oxidative stress through the regulation of Akt. Specifically, genetic inactivation of either eIF2αP or the ER-resident kinase PERK in primary mouse or human fibroblasts increases reactive oxygen species (ROS) production leading to increased DNA damage, Akt hyperactivation and induction of senescence. Contrary to the primary cells, immortalized and tumor cells are tolerant to elevated levels of intrinsic ROS caused by eIF2αP inactivation. Nevertheless, eIF2αP-deficient immortalized or tumor cells are more susceptible than eIF2αP-proficient cells to extrinsic oxidative stress caused by hydrogen peroxide or doxorubicin treatment. Extrinsic oxidative stress leads to the induction of either senescence or death in eIF2αP-deficient tumor cells in vitro and in vivo via impaired Akt activation. Our work concludes that Akt acts downstream of eIF2αP to convey either a pro-senescent or a pro-survival role in a cell-context dependent manner in response to oxidative stress. Also, eIF2αP is a potential pharmacological target for tumor treatment in combinational therapies with drugs that induce oxidative stress.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C51.
Citation Format: Antonis E. Koromilas, Rajesh Kamindla, Andreas I. Papadakis, Urszula Kazimierczak, Philippos Peidis, Shuo Wang, Clara Tenkerian, Jothi-Latha Krishnamoorthy, Maria Hatzoglou, Fawaz G. Haj, Gerardo Ferbeyre, Randal J. Kaufman. eIF2alpha phosphorylation determines cell susceptibility to oxidative stress via Akt activation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C51.