bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3366: The mechanical microenvironment and β1/FAK signaling control fibroblast accumulation in lung cancer
Authors: Alcaraz Jordi , Gabasa Marta , Busnadiego Óscar , Rodríguez-Pascual Fernando , Gascón Pere , Reguart Noemí 
Published: August 2015

Abstract
There is growing interest in targeting the abnormal accumulation of fibroblasts in solid tumors. The current paradigm assumes that the abundance of tumor associated fibroblasts (TAFs) is largely driven by soluble growth factors as in generic repair responses irrespective of the tumor type or subtype. We recently challenged this assumption in cultured TAFs from two major subtupes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQC). We reported that the increased population of SQC-TAFs is largely driven by matrix stiffening rather than by soluble growth factors. In contrast, ADC-TAFs were poorly responsive to exogenous mechanical cues. We also reported that the differential mechanoresponses in SQC- and ADC-TAFs were associated with both larger mechanosensing through FAK and β1 integrin expression in the former TAFs. To get more insights into the latter mechanoregulatory circuit, we forced either β1 integrin activation or FAK expression in fibroblasts cultured in soft (normal-like) gels. Both conditions were sufficient to increase fibroblast population to values comparable to those found in stiff (tumor-like) gels. These data reveal that an abnormally high intrinsic mechanosensing through β1 integrins and FAK can bypass the inhibitory (protective) role of an extrinsic soft microenvironment. Moreover, these results suggest that inhibiting either β1 integrin or FAK signaling may be a suitable approach to target tumor-supporting TAFs in SQC.
Citation Format: Jordi Alcaraz, Marta Gabasa, Óscar Busnadiego, Fernando Rodríguez-Pascual, Pere Gascón, Noemí Reguart. The mechanical microenvironment and β1/FAK signaling control fibroblast accumulation in lung cancer. [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 3366. doi:10.1158/1538-7445.AM2015-3366
Abstract 3370: Incorporation of mesenchymal stem cells into areas of lung metastasis in an osteosarcoma model
Authors: Gutierrez Luciana M. , Amoros Mariana A. , Sevlever Gustavo , Podahjcer Osvaldo , Cremaschi Graciela , Kleinerman Eugenie S. , Bolontrade Marcela F. 
Published: August 2015

Abstract
Lung is the most common metastatic site in osteosarcoma patients with a majority presenting lung micrometastasis at diagnosis time. MSCs compose a heterogeneous cell population with the ability to migrate and home into remodeling tissues, including tumors. To evaluate the participation of MSCs in lung metastasis formation, we intravenously injected LM7 osteosarcoma cells into immunosuppressed mice. Pre-labelled MSCs (DiR+/CMDiI+, at a dose of 0.5-1×10e6 cells) were intravenously administered 10 weeks after tumor cells injection, when microscopic metastasis become apparent. MSCs biodistribution was evaluated both through real time (DiR+) and microscopic (CMDiI+) analysis. MSCs levels in the lungs of tumor-bearing mice as compared to mice with no tumor burden was 1.15×10E5±0.07 p2/sec/cm2/sr vs. 5.44×10E4±0.5p2/sec/cm2/sr (one week post-inoculation, infrared signal, p&lt;0.01). This indicates a high homing ability of the stromal cells into the metastatic tumor microenvironment. Microscopic analysis corroborated infrared signal with MSCs presence and incorporation within the metastatic sites. In addition, MSCs displayed heterogeneous distribution within lungs with LM7 metastasis as opposed to the homogeneous MSCs distribution observed in lungs without metastasis. This suggests that MSCs are chemoattracted and retained in preferential areas within the lungs with LM7 osteosarcoma metastases. The setup of an experimental osteosarcoma metastatic model which incorporates administered MSCs as tumor stromal cells will be useful to analyze MSCs function in tumor metastasis formation.
Note: This abstract was not presented at the meeting.
Citation Format: Luciana M. Gutierrez, Mariana A. Amoros, Gustavo Sevlever, Osvaldo Podahjcer, Graciela Cremaschi, Eugenie S. Kleinerman, Marcela F. Bolontrade. Incorporation of mesenchymal stem cells into areas of lung metastasis in an osteosarcoma model. [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 3370. doi:10.1158/1538-7445.AM2015-3370
Abstract 3373: Identification of inflammation-related genes that regulate tumor-associated stemness using high-throughput siRNA screening
Authors: Xie Junling , He Huiwen , Chen Chong , Bai Lipeng , Wang Wei , Liu Yan , Guo Jian , Wu Peng , Xiang Rong , Luo Yunping 
Published: August 2015

Abstract
Cancer associated stem cells (CSCs) are considered to be responsible for tumor recurrence, metastasis as well as chemoresistance. These properties of tumor associated stemness are maintained by specialized microenvironment, including inflammation which is a key component of the tumor microenvironment. To study the relationship between inflammation and stemness of CSCs, here, we established a robust high-throughput RNAi screen platform for a global survey of inflammation-related genes affecting CSCs identity via alteration of Oct4 expression. Consequently, we found 72 novel genes from 1027 inflammation-related genes which could significantly affect OCT4 expression. These genes are functionally distinct including cytokines, adhesion molecules, apoptotic molecules, kinase, metabolism-related enzymes and transcriptional factors. Further, we carry out a functional validation of the 72 hits by mean of ALDEFLUORTM assay and we demonstrate that silence genes expression of IL-1A, IL-1B, ICAM3, CCL16, TRAF6, PRTN3, PDE3A, BCAR1, NFKB1 and IKK-β by siRNA would dramatically downregulate of the ALDH+ subpopulation cells. Moreover, we studied the functional roles of these factors on different kinds of tumor cell lines and mult-organ tumor tissue microarray. We observed that knockdown TRAF6 (TNF-α receptor associated factor 6) would reduce the expression of stemness associated genes SOX2, OCT4, NANOG, LIN28b, IKK-β β-catenin, and abate sphere-forming ability of breast cancer MDA-MB-231 cells, lung cancer A549 cells, liver cancer HepG2 cells and colon cancer SW-480 cells. It was also found that the expression of TRAF6 has a conspicuous relationship with multiple tumor occurrence and malignancy on tissue microarray. Most importantly, we found that knockdown the expression of TRAF6 could markedly suppressed tumor growth and metastasis of MDA-MB-231 in NOD/SCID mice model. Together, we uncovers a wealth of novel inflammatory regulators of CSCs by a high-throughput siRNA screen and validated the cytokine TRAF6 could govern tumor associated stemness in different tumors in vitro and in vivo, which would be a potential therapeutical target.
Citation Format: Junling Xie, Huiwen He, Chong Chen, Lipeng Bai, Wei Wang, Yan Liu, Jian Guo, Peng Wu, Rong Xiang, Yunping Luo. Identification of inflammation-related genes that regulate tumor-associated stemness using high-throughput siRNA screening. [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 3373. doi:10.1158/1538-7445.AM2015-3373
Abstract 3378: Discoidin domain receptor 2 differentially controls HT-1080 cell proliferation in young-adult and old type I collagen 3D matrices
Authors: Saby Charles , Garnotel Roselyne , El Btaouri Hassan , Van Gulick Laurence , Jeannesson Pierre , Morjani Hamid 
Published: August 2015

Abstract
Type I collagen plays a key role in tumor proliferation, adhesion and migration. We have recently demonstrated that this fibrillar and life-long protein undergoes detrimental changes in biochemical and biomechanical properties during aging (1). In addition to a high Advanced Glycation End-products (AGE) and cross-links content, old collagen exhibits a significant loss in fibrillar properties.
In this study, we analyzed the effect of collagen aging on human HT-1080 fibrosarcoma cell proliferation in 3D matrix model. For this, type I collagen was extracted from tail tendons of young-adult (2 months) and old (2 years) rats. In 3D matrix, the rate of HT-1080 cell growth was significantly lower in young-adult collagen. This was accompanied by a down-regulation of ERK1/2 phosphorylation and an increase in the cyclin-dependent kinase inhibitor p21 expression. Blocking antibodies and siRNA strategy against β1 integrin and AGEs receptor (RAGE) did not increase cell growth in young-adult collagen.
Accumulating evidence suggest that Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase with the unique ability to be activated by fibrillar collagen. To determine whether differential DDR2 responses are elicited by the two collagens, DDR2 was immunoprecipitated from cell lysates, and its phosphorylated form was detected by immunoblotting. DDR2 phosphorylation level was increased in young-adult collagen. This was accompanied by an increase in the tyrosine phosphatase SHP2 phosphorylation, the primary target of DDR2. Interestingly, the DDR2 inhibitor nilotinib was able to restore cell proliferation in young-adult collagen. In addition to an increase in ERK1/2 phosphorylation, nilotinib decreased SHP2 phosphorylation and p21 expression.
Taken together, these data show that age-associated changes of type I collagen organization, especially fibrillar properties, are critical for tumor cell proliferation control by DDR2.
References: (1) Wilson SL et al. FASEB J. 2014 28(11):14-25
Citation Format: Charles Saby, Roselyne Garnotel, Hassan El Btaouri, Laurence Van Gulick, Pierre Jeannesson, Hamid Morjani. Discoidin domain receptor 2 differentially controls HT-1080 cell proliferation in young-adult and old type I collagen 3D matrices. [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 3378. doi:10.1158/1538-7445.AM2015-3378
Abstract 3388: Analytical validation and clinical verification of phosphoprotein biomarker modulation using a novel preservation system-based flow cytometry assay in multiple myeloma clinical trials
Authors: Pahuja Anil , Sarikonda Shyam , Lee Benjamin , Graber Armin , Tangri Shabnam , Dakappagari Naveen 
Published: August 2015

Abstract
Propelled by the advent of novel oncogenic pathway-targeting drugs and increasing regulatory expectations to fulfil proof of mechanism endpoints in clinical trials, there is a critical need to reliably evaluate target inhibition by investigational drugs in biologically relevant compartments. However, the ability to monitor modulation of labile oncogenic pathway biomarkers in global hematomalignancy clinical trials is complicated by varying technical expertise at clinical sites, when specimen stability considerations do not permit analysis at a central specialty laboratory. To address this critical gap, we developed a novel preservation system, designated NovaPerm3 (NP3), that enables stabilization of phosphoprotein based biomarker specimens in a single step, requires less than 20 minutes, and can be implemented in routine clinical trial settings. Stabilized specimens can be frozen and analyzed even after 90 days in a specialized laboratory. Using the NP3 preservation system, we systematically developed and validated a flow cytometry assay that not only enables reliable identification of neoplastic plasma cells but also allows for quantitation of phosphoprotein biomarkers in the tumor cells of interest present in both the peripheral blood (PB) and bone marrow (BM). We will describe a) modulation of phosphorylation levels of the S6 ribosomal protein (pS6RP) by a novel anticancer agent in multiple myeloma patients b) qualitative concordance between NP3-flow cytometry and western blot results from multiple drug treated leukemia cell lines c) sensitive detection of neoplastic plasma cells up to 1% of the total white cells and d) specimen (pS6RP) stabilization over a 90 day period. In conclusion, our novel preservation method and clinical trial laboratory validated flow assay enables reliable quantification of signaling biomarkers in hematomalignancy trials with ease in a specialized central laboratory while reducing the procedural burden for collecting biomarker specimens in global clinical trials.
Citation Format: Anil Pahuja, Shyam Sarikonda, Benjamin Lee, Armin Graber, Shabnam Tangri, Naveen Dakappagari. Analytical validation and clinical verification of phosphoprotein biomarker modulation using a novel preservation system-based flow cytometry assay in multiple myeloma clinical trials. [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 3388. doi:10.1158/1538-7445.AM2015-3388
Abstract 339: Different receptor tyrosine kinases mediate EMT and erlotinib-resistance in NSCLC cell lines through bypass signalling
Authors: Raaby Jakobsen Kristine , Demuth Christina , Madsen Anne Tranbjerg , Westh Mortensen Birgit , Meldgaard Peter , Lade Nielsen Anders , Sandahl Soerensen Boe 
Published: August 2015

Abstract
Introduction: Erlotinib is a potent drug in the treatment of EGFR-driven lung cancer. Many patients initially benefit from erlotinib treatment, but nearly all acquires resistance and die of the disease. Several mechanisms related to erlotinib-resistance have been described including epithelial to mesenchymal transition (EMT). Signalling by TGFβ, Wnt or through receptor tyrosine kinases can initiate EMT, but not much is known about the trigger in relation to erlotinib-resistance. In this study, we investigate how EMT is initiated in two erlotinib-sensitive NSCLC cell lines developing erlotinib-resistance.
Methods: HCC827 (EGFR mutated) and Calu-3 (HER2 amplified) were treated with erlotinib in escalating concentrations (0.01 μM - 5 μM) over approximately 3 months, and erlotinib resistant (ER) sublines were established and investigated.
Results: Both HCC827ER and Calu-3ER gained EMT features including upregulation of SLUG, SNAIL and ZEB1. These changes were accompanied by increased IGF1R signalling in Calu-3ER and HCC827ER gained a MET amplification. To detect the relevance of MET and IGF1R signalling in accordance to EMT, we treated the cells with the tyrosine kinase inhibitors crizotinib (MET) and linsitinib (IGF1R). In both cases, we saw a decrease in EMT-marker transcription after the treatment. In addition, HCC827ER showed growth inhibition when treated with the MET-inhibitor crizotinib, but linsitinib did not inhibit the growth of Calu-3ER. Conclusion: Our study demonstrates how different receptor tyrosine kinase signalling pathways can induce EMT during the development of erlotinib-resistance. Furthermore, we show that EMT can accompany well-know resistance mechanisms such as MET-amplification and hereby contribute to the phenotype of the resistant cells.
Citation Format: Kristine Raaby Jakobsen, Christina Demuth, Anne Tranbjerg Madsen, Birgit Westh Mortensen, Peter Meldgaard, Anders Lade Nielsen, Boe Sandahl Soerensen. Different receptor tyrosine kinases mediate EMT and erlotinib-resistance in NSCLC cell lines through bypass signalling. [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 339. doi:10.1158/1538-7445.AM2015-339
Abstract 3404: NDRG2 suppresses growth and invasion of gallbladder carcinoma via regulation of matrix metalloproteinase 19/slug interaction
Authors: Kim Nayoung , Min Jeong-Ki , Kim Jin-Man , Lee Hyo Jin 
Published: August 2015

Abstract
Background: Gallbladder cancer is a relatively uncommon tumor worldwide but it has a feature of highly invasive and malignant tumor with poor prognosis. However, relevant molecules and/or genes associated with growth and metastasis of gallbladder carcinoma are poorly understood. Although NDRG2 is known as a tumor suppressor gene, its exact role in gallbladder carcinoma remains unknown.
Materials and method: For deciphering biological roles of NDRG2 in gallbladder carcinoma, first, we examined the expression of NDRG2 in tumor specimens from 86 gallbladder carcinoma patients by immunostaining and analyzed the correlation between NDRG2 expression and clinicopathologic parameters as well as patient survival. Second, we investigated the functional significance of NDRG2 in gallbladder carcinoma progression by stable knock-down or overexpression of NDRG2 in in vitro and in vivo studies.
Results: NDRG2 was differentially expressed in gallbladder carcinoma tissues. The negative expression of NDRG2 was significantly associated with a pathological T stage (P = 0.015), high histological grade (P = 0.020), and perineural invasion (P = 0.016). Multivariate analyses clearly showed that the loss of NDRG2 expression was an independent poor prognostic factor for cancer-specific survival. The stable expression of NDRG2 shRNA in gallbladder carcinoma cell lines significantly increased cell proliferation, anchorage-independent growth, migration and invasion. In addition, NDRG2 shRNA remarkably increased metastasis from the spleen to the liver in mice. Furthermore, loss of NDRG2 expression in cells caused an epithelial-mesenchymal transition through Slug induction by MMP-19 interaction with Slug promoter.
Conclusions: In the present study, we showed that loss of NDRG2 expression leads to poor prognosis and enhanced metastasis in gallbladder carcinoma. NDRG2 suppresses MMP-19 which causes an epithelial-mesenchymal transition through Slug induction. These data indicate that NDRG2 suppresses tumor progression via regulating MMP19/Slug axis in gallbladder carcinoma. The loss of NDRG2 is a novel prognostic factor suggesting it could be a useful biomarker in patients with gallbladder carcinoma and a potential therapeutic target.
Citation Format: Nayoung Kim, Jeong-Ki Min, Jin-Man Kim, Hyo Jin Lee. NDRG2 suppresses growth and invasion of gallbladder carcinoma via regulation of matrix metalloproteinase 19/slug interaction. [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 3404. doi:10.1158/1538-7445.AM2015-3404
Abstract 3407: FGFR4 Arg388 polymorphism is a poor prognostic factor for resected stage III colon cancer
Authors: Cho Sang-Hee , Shin Min-Ho , Kweon Sun-Seog , Kim Hee-Nam , Shim Hyun-Jeong , Hwang Jun-Eul , Bae Woo-Kyun , Chung Ik-Joo 
Published: August 2015

Abstract
Purpose To evaluate the prognostic role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in patients with surgically resected stage III colon cancer.
Patients and Methods FGFR4 polymorphism was checked in peripheral blood from 273 patients who received curative resection and diagnosed as stage III colon cancer. Genomic DNA was extracted from blood which was drawn before curative resection. FGFR4 Gly388Arg genotyping was carried out using high-resolution melting (HRM) analysis.
Results In total 273 patients, 92 patients (34%) were homozygous for Gly388 allele, with 146 heterozygous (54%) and 35 homozygous (13%) for Arg388. No significant association was found between clinical or histopathologic tumor characteristics and FGFR4 genotype. In survival analysis, Gly388 allele showed better 3Y-DFS than Arg388 carriers (heterozygous or Arg388 homozygous) in patients with no adjuvant (p = 0.26) or 5-FU/LV treated (p = 0.038). However, patients receiving adjuvant FOLFOX showed similar 3Y-DFS regardless of genotype. In addition, 5Y-OS was found significant improvement in Gly388 allele compared with Arg388 carriers (92.5% vs. 74.9%, p = 0.04) regardless of adjuvant treatment. In univariate analysis, age, N stage, tumor differentiation, lymphocyte response, adjuvant chemotherapy and FGFR4 genotype were associated with poor OS. In multivariate analysis, FGFR4 Arg388 carriers (HR 5.17; 95% CI, 2.06-12.92, p&lt;0.001) showed significantly poor prognostic factors for OS together with age (≥ 70Y), N stage, poorly differentiation, absence of lymphocyte response, no adjuvant chemotherapy.
Conclusion FGFR4Arg388 polymorphism is an independent poor prognostic factor in surgically resected stage III colon cancer. This result could guide the individual selection for adjuvant chemotherapy and potential therapeutic target for surgically resected stage III colon cancer.
Citation Format: Sang-Hee Cho, Min-Ho Shin, Sun-Seog Kweon, Hee-Nam Kim, Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Ik-Joo Chung. FGFR4 Arg388 polymorphism is a poor prognostic factor for resected stage III colon cancer. [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 3407. doi:10.1158/1538-7445.AM2015-3407
Abstract 341: Breast cancer cell adhesion and degradome interact to drive metastasis
Authors: Rizwan Asif , Cheng Menglin , Bhujwalla Zaver M. , Krishnamachary Balaji , Jiang Lu , Glunde Kristine 
Published: August 2015

Abstract
Although primary breast tumors are detected early in most cases, it is inevitable that many patients remain at risk for future recurrence and death due to micrometastases. We investigated the metastatic process with a focus on matrix metalloproteases (MMPs) within the degradome and on integrins and E-cadherin within the adhesome. We have performed comparative studies with a set of non-metastatic (BT-474, T47D, MCF7) versus metastatic (MDA-MB-231, SUM149, SUM159) human breast cancer cell lines and xenografts. Experiments were performed to measure growth rate, migration, invasion, and colony formation. Immunoblotting and immunohistochemistry revealed a higher expression of MMPs and heterophilic cell adhesion molecules integrin β1 and lower expression of homophilic cell adhesion molecule E-cadherin in the metastatic tumor cells and xenografts. Using zymography and activatable fluorescent probes for noninvasive imaging of MMPs, we demonstrated that metastatic breast cancer cells and tumors displayed an elevated degradome activity as compared to non-metastatic cells and tumors. Cell adhesion and cell aggregation assays showed an increased heterophilic and decreased homophilic adhesion in the metastatic models. Inhibiting MMPs reduced the expression of integrin β1, and stimulating integrin β1 resulted in higher MMP activities in metastatic cells. Re-expression of E-cadherin in metastatic cells led to a reduced expression of active integrin β1. Finally, circulating breast cancer cells and cells from lung metastatic nodules generated from metastatic tdTomato-fluorescing breast cancer cells displayed a reduced expression of active integrin β1 and less epithelial-mesenchymal-transition (EMT) marker protein S100A4. Our results indicate that proteolytic ECM remodeling by MMPs and cell adhesion by integrin β1 and E-cadherin are interdependent processes that control transformation from benign to invasive carcinoma and are critical for metastasis.
Citation Format: Asif Rizwan, Menglin Cheng, Zaver M. Bhujwalla, Balaji Krishnamachary, Lu Jiang, Kristine Glunde. Breast cancer cell adhesion and degradome interact to drive metastasis. [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 341. doi:10.1158/1538-7445.AM2015-341