bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4696: TRAF2 plays a critical role in maintaining lymphocyte homeostasis by regulating the basal activities of IKK and caspase-8
Authors: Zhang Laiqun , Blackwell Ken , Yeh Wen-Chen , Mak Tak Wah , Habelhah Hasem 
Published: June 2012

Abstract
TRAF2 and TRAF5 are RING domain proteins, and their RING domain-mediated RIP1 ubiquitination is believed to be essential for NF-κB activation and inhibition of caspase-8-mediated cell death in response to TNFα stimulation. We have previously reported instead that TRAF2/5 double knockout (DKO) cells exhibit high basal IKK activity in unstimulated conditions, and that TNFα stimulation further increases IKK activity in the absence of RIP1 ubiquitination in TRAF2/5 DKO cells. These findings potentially revise the currently accepted model for the role of TRAF2/5 in TNFα signaling. However, most of the conclusions in the field regarding the role of TRAF2/5 in TNFα signaling are based on the studies performed in immortalized MEFs, as TRAF2 KO mice die within 10 days after birth. Notably, elimination of either TNFα or TNFR1 enhances the survival of TRAF2 KO mice. Thus, to examine the role of TRAF2 in NF-κB activation versus cell death in primary cells, we generated TRAF2 KO and TNF/TRAF2 DKO mice. Surprisingly, both IKK and caspase-8 are constitutively activated to a certain degree in thymus and spleen, but not in muscle and liver, of one week old TRAF2 KO mice. In TNF/TRAF2 DKO mice, on the other hand, the basal caspase-8 activity is completely suppressed in thymus and spleen, while the basal IKK activity still remained high compared to that in wild-type mice. In addition, caspase-8 substrates such as RIP1 and cFLIP are constitutively cleaved in thymus and spleen, but not in muscle and liver, of TRAF2 KO mice, and these cleavages were completely inhibited in TNF/TRAF2 DKO mice. Functional assays performed in primary MEFs, bone marrow macrophages and T-cells revealed that TRAF2 suppresses basal IKK activity and p100 processing through the NIK-dependent and -independent pathways. Moreover, both the basal and TNFα-induced expression of anti-apoptotic proteins are normal in these primary cells isolated from TNF/TRAF2 DKO embryos and adult mice, yet these cells remain sensitive to TNFα-induced cell death, due to the impaired recruitment of cIAP1/2 to the TNFR1 complex in the absence of TRAF2. Collectively, these data demonstrate that TRAF2 maintains lymphocyte homeostasis by negatively regulating the basal activities of IKK and caspase-8 in thymus and spleen, and that TRAF2 inhibits TNFα-induced cell death by recruiting anti-apoptotic proteins to the TNFR1 complex rather than by activating the NF-κB pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4696. doi:10.1158/1538-7445.AM2011-4696
Abstract 4700: Identification and functional analysis of 9p23-24 amplified genes in human breast cancer
Authors: Wu Jack , Liu Suling , Liu Gang , Dombkowski Alan , Abrams Judith , Wicha Max , Ethier Stephen , Yang Zeng-Quan 
Published: June 2012

Abstract
Gene amplification is a major mechanism used by cancer cells to increase gene expression and subsequently gain a growth and survival advantage. Previously, we identified a novel amplicon at 9p23-24 region in human esophageal and breast cancer and originally cloned a novel gene GASC1 (Gene Amplified in Squamous Cell Carcinoma 1) from this amplicon. Accumulating evidence suggests common amplicons that occur in breast and other cancers contain multiple oncogenes that could play a role in cancer initiation and progression. In the current study, we aimed to comprehensively characterize the 9p23-24 amplified genes in human breast cancer. We performed array CGH analysis on a panel of cancer cell lines with the Agilent 244K microarray chip and narrowed the shortest region of overlapping (SRO) of the 9p23-24 amplicon to ∼2 Mb. Eleven genes within the SRO regions were examined for their mRNA expression by quantitative RT-PCR (qRT-PCR). Based on statistical association between copy number and expression, we confirmed GASC1 as a top candidate oncogene and identified three new potential oncogenes, UHRF2, KIAA1432 and C9orf123. Our more recent studies indicated that GASC1 is a member of a new class of oncogenes that are involved in the deregulation of histone methylation in cancer cells. We found that GASC1 induces the expression of core stemness transcription factors NANOG, SOX2 and OCT4, as well as classical oncogenes, including NOTCH1 and MYC, in breast cancer cells. On the other hand, UHRF2 encodes a nuclear protein that is involved in cell-cycle regulation. Knocking down UHRF2 slowed cell growth and inhibited colony formation of 9p23-24 amplified breast cancer cells. Furthermore, we demonstrated that expression levels of key tumor suppressing genes, including p16/INK4a, p21/WAF1 and p27/KIP1, were increased after knocking down UHRF2 in breast cancer cells. Collectively, our studies support the notion that the 9p23-24 amplicon contains multiple candidate oncogenes and may play an important role in human tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2011-4700
Abstract 4703: Mitochondrial DNA mutations affect respiratory complex-I in never-smoker lung cancer patients and contribute to lung cancer cell growth
Authors: Dasgupta Santanu , Soudry Ethan , Shao Chunbo , Mukhopadhyay Nitai D. , Yee John , Lam Stephen , Lam Wan L. , Fisher Paul B. , Sidransky David 
Published: June 2012

Abstract
Lung cancer is a deadly disease worldwide with smoking being the most important risk factor. In the United States, it is estimated that there will be over 222,550 cases of lung cancer resulting in 157,300 deaths in 2010. Despite significant improvement in therapeutic modalities, the overall 5-year survival rate is still only 15%. The high morbidity is due to the lack of early detection and therapeutic intervention. Other than nuclear genetic alterations, mitochondrial DNA mutations were reported in different human cancers and implicated to have a potential role in biomarker development. However, mtDNA alteration patterns and their potential involvement are unknown in lung cancer patients that have never smoked. In the present study, we sequenced the entire mitochondrial genome and measured the mtDNA content index by quantitative PCR in 60 lung cancer patients. Of the 60 patients, 30 never smoked and the remaining 30 patients were current smokers. Forty five percent of patients (27/60) displayed at least one somatic mtDNA mutation and a total of 41 mutations were detected which were mostly homoplasmic in nature. Strikingly, mtDNA mutations were significantly higher (P=0.0025) among the non-smokers as compared to the current smoking lung cancer patients and these mutations significantly affected (P=0.025) mitochondria encoded respiratory complex-I. The patients of Asian origin also had significantly higher (P=0.015) mtDNA mutations compared to the Caucasian patient populations. The mtDNA content index also significantly increased (P=0.037) in the non-smokers compared to the smoker lung cancer patients. Forced overexpression of a frequently observed mtDNA mutation from the ND5 gene of respiratory complex-I resulted in increased superoxide production, in vitro proliferation and invasion of lung cancer cells. Frequent mtDNA alterations are detectable in non-smoker lung cancer patients and may contribute to lung cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4703. doi:10.1158/1538-7445.AM2011-4703
Abstract 473: CD4+ T cell help differentially influences anti-tumor immunity as a function of T cell avidity
Authors: Zhu Ziqiang , Singh Vinod , Bronte Vincenzo , Feigenbaum Lionel , Hurwitz Arthur 
Published: June 2012

Abstract
One of the major hurdles for cancer immunotherapy is that most tumors express self-antigens to which the immune system is unresponsive due to self-tolerance. Our lab and others have demonstrated that high-avidity tumor-specific CD8+ T cells are superior in anti-tumor activity to low avidity T cells. However, adoptive transfer of high-avidity, tumor-specific CTL populations may fail due to loss of CTL effector functions upon tumor infiltration. Therefore, strategies to maintain effector functions of high avidity CTL, or enhancement of low avidity CTL are desirable. To investigate whether provision of CD4+ T cell help will enhance the effectiveness of high-avidity CTLs in anti-tumor immunity as compared to lower avidity T cells, we utilized two transgenic mouse lines developed in our lab that bear different TCR transgenes specific for a common melanoma differentiation antigen, tyrosinase-related protein 2 (TRP-2(180-188)). T cells from clone 24 TCR Tg mice (TCRhi) show higher avidity than those from clone 37 (TCRlo) mice based on tetramer dissociation and in vitro effector function assays. Here we report that co-activation of CD4+ T cells (OVA323-339 specific, CD4-OVA) with TRP-2-specific CD8+ T cells can boost the in vitro function of TCRhi cells, including proliferation, IFN-γ secretion, Gr-B secretion as well as cell-mediated cytotoxicity, but had minimal effect on TCRlo cells. We observed that only adoptive co-transfer of CD4-OVA cells with TCRhi cells suppressed tumor growth of (5 day) established B16 melanoma tumors. Furthermore, those mice receiving co-transferred CD4-OVA cells with TCRhi cells developed autoimmune depigmentation at the sites of vaccination and tumor challenge. Our finding may have important implications for enhancement of cancer immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 473. doi:10.1158/1538-7445.AM2011-473
Abstract 4739: Mesenchymal stem cells induce broad spectrum resistance to chemotherapy through the release of platinum-induced fatty acids
Authors: Roodhart Jeanine M.L , Daenen Laura G. , Stigter Edwin C. , Ishihara Kenji , Medema Rene H. , Brenkman Arjan B. , Voest Emile E. 
Published: June 2012

Abstract
Background The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. It is becoming increasingly clear that the tumor micro-environment plays a key role in the development of drug resistance. Mesenchymal stem cells (MSCs), key players in tissue repair and wound healing, are recruited in large numbers to the stroma of developing tumors where they are known to support tumor growth and enhance metastasis formation.
Aim To determine whether MSCs confer resistance to chemotherapy, we established different murine tumor models in which we resembled the mobilization and recruitment of MSCs from the bone marrow to tumor.
Results Administration of 50,000 MSCs intravenously (iv), or as little as 1,000 MSCs subcutaneously (sc) together with chemotherapy almost completely abolished the anti-tumor effect of the chemotherapy in a dose-dependent matter. Notably, this was only observed with the platinum-based chemotherapeutics, namely cisplatin, oxaliplatin and carboplatin. To show that the MSCs induce resistance in a paracrine fashion, we incubated cultured MSCs with platinum-based chemotherapy and injected the conditioned medium (CM+) from these cells sc concomitantly with the chemotherapy. Strikingly, the CM+ induced an almost complete resistance to multiple types of chemotherapy, including non-platinum based chemotherapeutics like 5-FU and irinotecan. The CM from untreated MSCs (CM-), did not induce resistance. Through a metabolomics approach, we identified two unique platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT(n-6)) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)) in the CM+ responsible for the induction of resistance by the MSCs. We tested the purified PIFAs in our mouse models and confirmed that in minute quantities (2pmol) these PIFAs induce resistance to a broad spectrum of chemotherapy. In contrast, other related poly-unsaturated fatty acids had no effect.
Conclusion In summary, our study identifies a novel paracrine mechanism of resistance via activation of MSCs by platinum-based chemotherapy with the subsequent release of two specific resistance-inducing PIFAs. Our findings suggest that interventions directed against either MSC or the identified PIFAs may be explored to enhance the efficacy of chemotherapy and prevent the development of resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4739. doi:10.1158/1538-7445.AM2011-4739
Abstract 4749: Aligned collagen is a prognostic signature for survival in human breast carcinoma
Authors: Conklin Matthew W. , Eickoff Jens C. , Riching Kristin M. , Pehlke Carolyn A. , Eliceiri Kevin W. , Provenzano Paolo P. , Andreas Friedl , Keely Patricia J. 
Published: June 2012

Abstract
Evidence for the potent influence of stromal organization and function on invasion and metastasis of breast tumors is ever growing. Here we have performed a rigorous examination of the relationship of a tumor-associated collagen signature (TACS-3), to the long term survival rate of human patients. TACS-3 is characterized by bundles of straightened and aligned collagen fibers that are oriented perpendicular to the tumor boundary. An evaluation of TACS-3 was performed in biopsied tissue sections from 196 patients by second harmonic generation (SHG) imaging of the backscattered signal generated by collagen. Univariate analysis of a Cox proportional hazard model demonstrated that the presence of TACS-3 was associated with poor disease-specific and disease free survival, resulting in hazard ratios between 3.0-3.9. Furthermore, TACS-3 was confirmed to be an independent prognostic indicator regardless of tumor grade and size, ER or PR status, HER-2 status, node status, and tumor subtype. Interestingly, TACS-3 was positively correlated to expression of stromal syndecan-1, a receptor for several extracellular matrix proteins including collagens. Because of the strong statistical evidence for poor survival in patients with TACS, and since the assessment can be performed in routine histopathologic samples imaged via SHG or using picrosirius, we propose that quantifying collagen alignment is a viable, novel paradigm for the prediction of human breast cancer survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4749. doi:10.1158/1538-7445.AM2011-4749
Abstract 475: Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells
Authors: Damelin Marc I. , Geles Kenneth G. , Follettie Maximillian T. , Yuan Ping , Baxter Michelle , Golas Jonathon , Huang Shuguang , DiJoseph John , Diesl Veronica , Behrens Carmen , Choe Sung E. , Rios Carol , Gruzas Janet , Sridharan Latha , Dougher Maureen , Kunz Arthur , Hamann Philip R. , Evans Deborah , Armellino Douglas , Khandke Kiran , Marquette Kimberly , Tchistiakova Lioudmila , Boghaert Erwin , Abraham Robert T. , Wistuba Ignacio I. , Zhou Bin-Bing S. 
Published: June 2012

Abstract
Poorly differentiated tumors in non-small cell lung cancer (NSCLC) are refractory to chemotherapy and associated with short survival time. Here we integrate multiple experimental models with clinicopathological analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We demonstrate that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition was observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 475. doi:10.1158/1538-7445.AM2011-475
Abstract 4761: Regulation of TNFα-induced cell death of primary human brain microvessel endothelial cells by integrins
Authors: Rani M R Sandhya , Huang Ping , Prayson Richard , Hedayat Hirad , Sloan Andrew E. , Nowacki Amy , Weil Robert , Ahluwalia Manmeet S. , Tipps Russell , Gladson Candece L. 
Published: June 2012

Abstract
TNFα induces cell death of primary human brain microvessel endothelial cells (MvEC) in a dose-dependent manner through TNF-R1 activation. To determine whether TNF-R1 was available to be therapeutically manipulated on tumor-associated endothelial cells in glioblastoma tumors, we evaluated its expression on the endothelial cells in 50 human glioblastoma and 38 normal brain samples by immunohistochemistry. A significantly increased expression of TNF-R1 and TNFα was detected on the endothelial cells in the tumor biopsies as compared to the normal brain samples. We then investigated whether integrins regulate TNF-R1 pro-apoptotic signaling in MvEC isolated from normal brain; these cells proliferate in culture and resemble reactive endothelial cells. TNFα stimulation readily induced cell death of the brain MvEC when plated on collagen or fibronectin (attachment mediated by integrins α2β1 and α5β1, respectively), but the cells were protected from this pro-death signal when plated on laminin (mediated by integrin α6β1). In the cells plated on collagen (not on laminin) a time-dependent increase in the phosphorylation of p38 MAP kinase was detected with TNFα stimulation and knockdown of p38 MAP kinase blocked the TNFα-induced cell death suggesting p38 MAP kinase is a downstream effector for TNFα-induced apoptosis. We then examined whether engagement of a particular integrin signaled for expression of an anti-apoptotic protein and found expression of cFLIP when the MvEC were plated on laminin, but not when the cells were plated on collagen. Furthermore, down-regulation of cFLIP using siRNA restored the pro-apoptotic signal of TNFα in MvEC plated on laminin. To substantiate the clinical relevance of these findings, we examined the effect of TNFα stimulation on endothelial cells isolated from two different glioblastoma tumors, and found that TNFα induced cell death was similarly regulated by the ECM or integrins. Our data suggest that TNF-R1 on tumor-associated endothelial cells in glioblastoma tumors is available to be therapeutically manipulated as part of an anti-angiogenic therapy, and that the effectiveness of such a therapy maybe in part dependent on the activity of specific integrins expressed on the tumor endothelial cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4761. doi:10.1158/1538-7445.AM2011-4761
Abstract 4764: The LTbR mediates immune cell-exerted anti-tumor cytotoxicity
Authors: Hu Xiaolin , Liu Kebin 
Published: June 2012

Abstract
Lymphotoxin beta Receptor (LTβR) belongs to the Tumor Necrosis factor (TNF) receptor superfamily and was originally identified to be critical for the development and maintenance of secondary lymphoid architectures. However, it is increasingly appreciated that the LTβR signaling pathway is involved in induction of extrinsic apoptotic cell death in tumor cells. Strikingly, it was recently observed that sustained expression of LTβR ligands also promote tumor development via a NF-κB-dependent mechanism. Thus, LTβR could function as two-edged sword. There are two physiological ligands, LTα1LTβ2 and LIGHT, that engage the LTβR to initiate signaling transduction. These two ligands are known to be expressed in immune cells. However, whether immune cells use these two ligands to suppress tumor development is unknown. In this study, we observed that LTβR protein in expressed in all tumor cell lines examined and in human colon carcinoma and sarcoma specimens. Engagement of the LTβR with LTβR-specific agonist mAbs activated both the canonical and alternative NF-κB signaling pathways in tumor cells. However, these agonist mAbs at the same time also effectively suppressed the growth of colon carcinoma, melanoma, mammary carcinoma and sarcoma cells in vitro, suggesting that the LTβR-mediated apoptosis signaling pathway overpowers the LTβR-initiated NF-κB signaling pathways to yield an overall tumor suppressive effect. Furthermore, both LTα1LTβ2 and LIGHT were activated in tumor-infiltrating macrophage, NK and T cells. Chimera mice with LTα-, LIGHT- or both LTβ and LIGHT-deficient immune cells exhibited significantly high incidence of MCA-induced tumor and greater tumor growth than chimera mice with wt immune cells. Furthermore, double-deficiency of LTβ and LIGHT in the immune cells resulted in significantly higher tumor incidence and greater tumor growth than LTα-deficiency alone. Taken together, our data suggest that LTβR mediates an immune cell-exerted anti-tumor effector mechanism in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4764. doi:10.1158/1538-7445.AM2011-4764