bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5204: Mechanisms of Notch4-Nodal regulation of the aggressive melanoma phenotype
Authors: Hardy Katharine M. , Kirschmann Dawn A. , Seftor Elisabeth A. , Kirsammer Gina T. , Strizzi Luigi , Hendrix Mary JC 
Published: August 2012

Abstract
Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. The current lack of effective therapies for treating metastatic melanoma exemplifies the desperate need for the identification of new targets and the development of new therapies. Nodal is an embryonic signaling molecule from the TGFβ superfamily that is not typically expressed in adult tissues but is reactivated in a number of aggressive cancers including melanoma, and breast and prostate carcinomas. In a study recently published by our group, we determined a connection between the Notch and Nodal pathways in aggressive melanoma. We identified a specific correlation between the expression of Notch4 and Nodal in aggressive melanoma cell lines and in advanced stage human melanomas. By inhibiting Notch4 expression or function, we established a link between Notch4 and Nodal signaling in promoting the aggressive phenotype of metastatic melanoma cells in vitro. Notch4 regulation of Nodal expression was identified as important in cellular plasticity, since inhibition of Notch4 function impaired the ability of aggressive cells to engage in vasculogenic mimicry (de novo formation of vascular-like networks by non-endothelial tumor cells). Notably, vascular-like network formation could be partially rescued by recombinant human Nodal, suggesting both pathways are important for this phenomenon. To extend our published observations, we utilized neutralizing antibodies to Notch4 and to Nodal, and compared gene expression profiles. From this, we identified a mechanism of feedback between signaling pathways that controls the expression of components of both pathways, including Nodal, Notch4, and the Notch ligand, Jagged2. Since Notch4 is enriched in the subpopulation of cells that form vascular-like networks in melanoma, we specifically analyzed the expression of angiogenesis signature genes previously associated with vascular-like network formation, and determined that inhibition of Notch4 or Nodal function downregulates a large group of these genes including members of the VEGF, angiopoietin, MMP, and cadherin families. We are currently investigating the hypothesis that the Notch4-Nodal signaling axis may be a master regulator of the vascular-like phenotype in aggressive melanoma cells. We suggest that inhibition of Notch4 and/or Nodal function may offer a potential molecular targeting strategy for metastatic melanoma therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5204. doi:1538-7445.AM2012-5204
Abstract 5208: Overexpression of EZH2 increases multipotent mammary stem cell self-renewal and differentiation
Authors: Li Xin , Toy Katherine , Kleer Celina G. 
Published: August 2012

Abstract
BACKGROUND: A role for EZH2 in stem cell maintenance was recently reported. Our lab has previously demonstrated that overexpression of EZH2 accelerates the initiation of ErbB2-induced mammary tumors. To understand underlying mechanism, we investigated the role of EZH2 in regulation of stem cells and luminal progenitor cells utilizing xenotransplantation studies of preneoplastic mammary glands of EZH2+; neu and EZH2 wt; neu transgenic mice. METHODS: Generation of crossing EZH2+; neu and EZH2 wt; neu transgenic mice was described previously. Mouse handling and experimental procedures were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the IACUC of the UM. Stem cells (Lin-/CD49f+/ESA-) and luminal progenitor cells (Lin-/CD49f+/ESA+) were isolated from the hyperplastic mammary glands of 8 weeks old EZH2+; neu and EZH2 wt; neu mice by flow cytometry (n=15 per group). Stem cells and luminal progenitor cells were injected into cleared fat pads of 3 weeks old FVB mice. After 5 weeks the mammary glands were subjected to flow cytometry and histology. RESULTS: Histologic study showed that only the stem cells, but not the luminal progenitor cells, extracted from EZH2+; neu and EZH2 wt; neu transgenic mice were able to form mammary outgrowths. Outgrowths of EZH2+;neu mice had significantly increased epithelial proliferation and increased numbers of terminal end buds (p&lt;0.05) compared to EZH2 wt;neu outgrowths. EZH2 +;neu outgrowths had significant upregulation of Ki67 and pSTAT5 proteins. Flow cytometry of the outgrowths revealed that while all cell populations were increased, EZH2 induced a more pronounced expansion of the stem cell and luminal progenitor cell populations. CONCLUSIONS: Our data show that EZH2 overexpression in ErbB2 mice induces an expansion of the multipotent mammary stem cell population with the ability to regenerate the cellular heterogeneity of the mammary gland and develop hyperplastic outgrowths. We found that EZH2 promotes hyperproliferation and upregulation of STAT5 phosphorylation in the mammary epithelium in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5208. doi:1538-7445.AM2012-5208
Abstract 5214: Functional interaction between foxm1 and β-catenin
Authors: Gong Aihua , Yu Guanzhen , Zhang Nu , Wei Ping , Aldape Kenneth D. , Colman Howard , Xue Jianfei , Liu Mingguang , Sawaya Raymond , Xie Keping , Yung W.K. Alfred , Medema René H. , He Xi , Huang Suyun 
Published: August 2012

Abstract
The Wnt/β-catenin signaling pathway is aberrantly activated in human cancers and is critical for cancer formation, but its molecular mechanisms are not fully understood. In the current study, we found that FoxM1, which is also activated in most human tumors, is a novel downstream component of Wnt signaling and is critical for β-catenin transcriptional function in tumor cells. Wnt increases the level and nuclear translocation of FoxM1 through inhibition of FoxM1 protein degradation. FoxM1 binds directly to β-catenin and enhances β-catenin nuclear localization and transcriptional activity. Moreover, FoxM1, β-catenin and TCF-4 are mutually recruited to Wnt target-gene promoters, and FoxM1 promotes the assembly of the β-catenin-TCF transcription activation complex in the promoters hence the Wnt target gene expression. Furthermore, interaction of FoxM1 and β-catenin plays a critical role in glioma stem cell self-renewal and differentiation and is required for glioma formation. Finally, the expression levels of nuclear β-catenin in human GBM directly correlates with levels of nuclear FoxM1, supporting the critical role of FoxM1 in β-catenin activation in human GBM. Given the importance of FoxM1 and the Wnt/β-catenin signaling pathway in human cancers in general, our findings not only provide an improved understanding of the molecular mechanisms underlying Wnt/β-catenin activation and tumorigenesis but also suggest additional targets for therapeutic intervention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5214. doi:1538-7445.AM2012-5214
Abstract 5215: EZH2-mediated STAT3 activation in glioblastoma
Authors: Kim Eunhee , Woo Dong-Hun , Lee Jeongwu 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor despite maximal therapy. Recent studies suggest that GBMs contain highly tumorigenic, stem cell-like cells termed glioblastoma stem cells (GSCs). GSCs significantly contribute to tumor propagation and treatment resistance and thus are critical target for curative therapy in GBMs. These GSCs share a key characteristic of normal stem cells, such as unlimited self-renewal capacity. Maintenance of the stem cell status in normal stem cells is governed by the Polycomb Repressive Complex 2 (PRC2)-mediated transcriptional repression. Enhancer of zeste homolog 2 (EZH2) is the only catalytically active component in PRC2, and it methylates a specific lysine residue of histone 3, resulting in the repressive chromatin structure. Signal transducer and activator of transcription 3 (STAT3) regulates diverse cellular processes and is frequently activated during tumorigenesis. Components of PRC2 are highly expressed in various cancers including GBMs and STAT3 is required for GSCs maintenance. In this study, we investigated the functional interaction between these two oncogenic pathways regulating GSCs phenotype. We show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor called 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA) inhibits STAT3 activity. Furthermore, AKT-mediated EZH2 phosphorylation affects STAT3 activity through STAT3 methylation. We demonstrate that STAT3 bind to EZH2 promoter and inhibition of STAT3 activity by small molecule inhibitor decrease PRC2 protein expression. Targeting of EZH2 and STAT3 by combined treatment with DZNep and STAT3 inhibitor strongly impairs GSCs self-renewal in vitro and decreases markers of neural stem cell multipotency. In addition, shEZH2 transduction + STAT3 inhibitor treatment extend survival of SCID mice with intracranial GSCs than shEZH2 single transduced group. Together, these obtained results strongly suggest the presence of positive feedback activation loop between PRC2 and STAT3 signaling in GSCs and targeting of this activation loop may offer an attractive therapeutic strategy for GBM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5215. doi:1538-7445.AM2012-5215
Abstract 5223: The role of bone-marrow derived cells in the intestinal tumor microenvironment of apcmin/+ mouse on tumor response to inhibitors of thymidylate synthase
Authors: Acharya Grishma , Davis Celestia , Tisdale Nikeya , Zhang Yu , Pena Maria Marjorette O 
Published: August 2012

Abstract
The vast majority of chemotherapeutic agents have been developed to specifically target actively dividing neoplastic cells. However, tumors are not exclusively composed of a heterogeneous population of neoplastic cells. They also include a heterogeneous collection of host derived infiltrating non-neoplastic cells that together with the extracellular matrix and secreted molecules compose the tumor stroma or microenvironment. Multiple interactions between stromal and tumor cells play a critical role in tumor growth and progression. Therefore, tumor response to chemotherapy and recurrence post-therapy must also be influenced by these interactions. For many decades, inhibitors of the enzyme thymidylate synthase (TS), such as fluoropyrimidines, have been used in the clinical management of various cancers; however, their clinical efficacy continues to be limited by their toxicity to normal cells and acquired resistance by tumor cells. Therapeutic efficacy is often measured by its impact on tumor burden, however, the impact of TS inhibitors on tumor stromal cells and their role on tumor response to therapy is largely unknown. The goal of this project is to determine the role of bone marrow derived tumor stromal cells (BMDCs) in mediating tumor response to systemic therapy with TS inhibitors. We hypothesize that, in addition to targeting tumor cells, TS inhibitors also directly target stromal cells and that the sensitivity of stromal cells to the therapy determines tumor response. Using the ApcMin/+ mouse as a model of intestinal tumorigenesis, we identified and characterized BMDCs in the intestinal tumor stroma. These included Macrophages, Fibroblasts, Pan T cells, Helper T cells, Leukocytes, Mast cells, T-regulatory cells (T-reg) and Myeloid derived suppressor cells (MDSCs), among others. We generated chimeric mice wherein the chemosensitivity of intestinal tumor cells to TS inhibitors was distinct from that of the BMDCs by transplanting eGFP positive bone marrow cells that were genetically modified to express a drug resistant variant of TS. We examined the effect of 5-FU on MDSCs, mast cells, and T-regs, that have previously been shown to promote intestinal tumor development in ApcMin/+ mice. The results showed that MDSCs were specifically sensitive to 5-FU due to its apoptotic effect on these cells. Current studies are aimed at identifying the combination of stromal cells that mediate tumor response to TS inhibitors in order to identify cellular targets for combined therapy that would enhance reduction of tumor burden or delay tumor recurrence.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5223. doi:1538-7445.AM2012-5223
Abstract 5225: Correlation between αvβ3 integrin expression, paclitaxel resistance and RGD-bearing conjugate efficacy
Authors: Eldar-Boock Anat , Sanchis Joaquin , Lupu Ruth , Vicent Maria J. , Satchi-Fainaro Ronit 
Published: August 2012

Abstract
Overcoming drug resistance, emerging either on recurring cancer or metastasis, is a major target of cancer treatments. The combination of anti-angiogenic therapy with cytotoxic therapy offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug, which also exhibits anti-angiogenic activity at low doses. The use of the hydrophobic PTX to its full potential is limited by severe side effects, caused by the drug and its solubilizing agents. Integrins play a key role in cell matrix interactions. The highly restricted expression of integrin αvβ3, overexpressed on tumor endothelial and some epithelial cells, during tumor growth, invasion, and metastasis present an interesting molecular target for metastatic breast tumors. In addition, PTX acquired resistance correlated with integrin αvβ3 overexpression on breast cancer cells. We designed and synthesized a novel polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. Polymer conjugation converted PTX to a water-soluble macromolecule, which passively targeted the tumor tissue exploiting the enhanced permeability and retention (EPR) effect, while extravasating via the leaky tumor neovasculature. The E-[c(RGDfK)2] enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the αvβ3 integrin. PGA is enzymatically-degradable by cathepsin B, leading to PTX release. PGA-PTX-E-[c(RGDfK)2] displayed a potent anti-angiogenic therapy, determined by several, well-established, in vitro assays. Mice bearing orthotopic mammary tumors demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decreased in toxicity compared with free PTX. The correlation between αvβ3 integrin expression on tumor cells and acquired PTX-resistance was determined by in vitro manipulation of αvβ3 overexpressing-cells and by examining subsets of primary versus metastatic or recurring tumors of PTX-treated patients as well as free and conjugated-PTX-treated tumor-bearing mice. Taken together, our conjugate alters the pharmacokinetics of free PTX. Inclusion of an active targeting moiety to integrin expressing-cells, have the potential to manipulate and overcome acquired drug resistance, which will hopefully warrant it as a novel targeted, anti-angiogenic and anticancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5225. doi:1538-7445.AM2012-5225
Abstract 5230: Improving the specificity of drugs which target the actin cytoskeleton for cancer therapy
Authors: Sequeira Vanessa B. , Stehn Justine R. , Haass Nikolas , Bonello Teresa , Guven Kim , Desouza Melissa , Schevzov Galina , Kottyan Gregg , McCluskey Adam , Bischof Leanne , Palmer Stephen , Hardeman Edna C. , Allanson Munif , Reeve Vivienne , Weninger Wolfgang , Cripe Timothy P. , Gunning Peter 
Published: August 2012

Abstract
The actin cytoskeleton is fundamental in the regulation of cellular processes involved in tumourigenesis and is therefore a highly desirable chemotherapeutic target. However, the non-specific nature of actin-targeting drugs makes them ineffective due to their toxic action on the heart. We have designed a class of drugs that target the second core component of actin filaments, tropomyosin. Tm5NM1, a cytoskeletal tropomyosin isoform, is upregulated in a variety of tumour cells and patient samples, and is known to promote tumour cell growth. Our lead drug, TR100, targets Tm5NM1 and potentially other isoforms, reducing cell proliferation in vitro in a panel of melanoma and neuroblastoma cell lines and decreases the rate of tumour growth in vivo in melanoma and neuroblastoma mouse models without affecting heart integrity. The difficulty in improving the specificity of these anti-tropomyosin compounds for Tm5NM1 was the lack of a suitable cell-based system to test the drugs. NIH3T3 stable cells overexpressing fluorophore-tagged Tm5NM1 or the muscle-specific isoform αfastTm now allows us to determine the impact of our drugs on functionally distinct actin populations. Since tropomyosin is a structural protein with no known measurable catalytic activity it has previously been challenging to design a high throughput assay to quantitate specific changes in actin filament architecture. High content imaging provides a system to image actin filament integrity which can be quantified using an algorithm designed in collaboration with the CSIRO. Using this algorithm we can calculate the impact of the anti-tropomyosin compounds on actin filaments in co-cultured stable cells. Development of these assays will contribute to the design of more specific drugs which target defined tropomyosin containing actin populations highly expressed in cancer without showing toxicity in muscle, thereby improving the therapeutic index of anti-tropomyosin drugs for the clinical treatment of a wide array of cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5230. doi:1538-7445.AM2012-5230
Abstract 5234: Microenvironmental signals dictate disseminated tumor cells (DTCs) fate through regulation of TGFβII and p38α
Authors: Bragado Paloma , Estrada Yeriel , Sosa Maria Soledad , Schewe Denis M. , Capobianco Carla , Moore Kateri , Farina Hernan G. , Aguirre-Ghiso Julio 
Published: August 2012

Abstract
Metastases develop from disseminated tumor cells (DTCs) years or even decades after primary tumor treatment. This is thought to be due to the ability of residual DTCs to remain dormant, but the mechanisms controlling this state are poorly understood. We have explored whether the target organ microenvironment where DTCs lodge can control their fate and the timing of DTCs dormancy in a HNSCC model. When injected in nude mice, HEp3-GFP cells form tumors with 100% efficiency and spontaneously disseminate to lungs (72% incidence) and bone marrow (BM) (28% incidence). Tracking of GFP-tagged DTCs showed that after ∼2 weeks the quiescent DTCs in lungs start to grow to form overt metastasis in 72% of mice. In contrast, those in the BM remain at constant numbers suggesting a dormant phenotype. Furthermore, DTCs isolated from lungs and expanded in culture (Lu-HEp3) display a high ERK/p38 signaling ratio and are tumorigenic when inoculated in vivo. Meanwhile in vitro expanded BM-HEp3-derived cell lines remain dormant when inoculated in vivo and are characterized by a low ERK/p38 activity ratio (predictive of quiescence for breast fibrosarcoma, squamous carcinoma and colon carcinoma cells) and by increased expression of the key dormancy transcription factors (TFs) Sharp1 and p53. In addition, treatment of THEp3 cells with BM conditioned media inhibits in vivo proliferation, activates TGFβ2 and p38α, and induces the expression of Sharp1 and p53. Moreover, inhibition of TGFβ signaling using a TGFβRI inhibitor, blocks p38 activation and downregulates Sharp1 and p53 in BM-HEp3 cells, suggesting that BM-HEp3 cells dormancy is functionally linked to TGFβ signaling. Importantly, TGFβ2, p38α or Sharp-1 knock down interrupted BM-HEp3 cell dormancy, while overexpression of p38α inhibits lu-HEp3 cells in vivo growth. In addition to that, systemic inhibition of p38α/β with SB203580 or TGFβRI/II with LY364947, dramatically accelerated lung metastasis as well as DTCs, micro- and macro-metastasis burden in growth restricted sites such as, spleen, liver or BM. We propose that reprogramming of DTCs into dormancy in growth restrictive microenvironments might induce a gene network activated by stress signaling mediated at least by TGFβ2 and p38α/β signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5234. doi:1538-7445.AM2012-5234