bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1510: Blockade of the mTOR/NF-κB signaling axis augments prostate cancer treatment responses through suppression of a microenvironment-derived DNA damage secretory program
Authors: Sun Yu , Coleman Ilsa , Nelson Peter 
Published: August 2012

Abstract
Background/Rationale: Resistance to cytotoxic chemo- and radiotherapy is a common event in advanced prostate cancers. While resistance is established as a consequence of cancer cell intrinsic genetic and epigenetic changes, emerging evidence indicates that therapy failure is also caused by cell extrinsic factors such as cytokines, growth factors, proteases and other soluble ligands generated from damaged stromal cells in the tumor microenvironment (TMEN). We recently reported a unique feature of stromal cells, namely a DNA damage secretory phenotype (DDSP) resulting from genotoxic therapeutics. Thus, anti-cancer therapies that cause DNA damage responses (DDR), unexpectedly, trigger pro-survival signaling in neoplastic or pre-neoplastic cells and may promote subsequent therapy resistance. Results: In this study, we show that molecular inhibition of the mammalian target of rapamycin (mTOR) through genetic or chemical approaches suppresses a cellular secretory program resulting from exposure to genotoxic agents. We identified a physical association between mTOR and the I-kappa-B kinase (IKK) complex which is activated by DNA damage stimuli, and found IKKα to be the major subunit that directly interacts with mTOR while assembling the IKK complex. Rapamycin abrogates IKKα phosphorylation, IαBβ degradation and the central action-p65/p50 nuclear translocation. Thus, IKK catalytic subunits are not equally implicated in propagating damage signals to NF-κB, with IKKα playing the pivotal role. We determined that the mTOR/Raptor complex is activated by genotoxic stress and promotes NF-κB signaling. Suppressing mTOR dramatically abolished transcriptional levels of NF-κB target genes. We also determined that paracrine-acting DDSP factors are regulated through both transcriptional and post-transcriptional mechanisms, as upregulation of S6K and downregulation of 4E-BP1 play essential and synergistical roles in synthesis of DDSP factors. Finally, we determined that mTORC1 is the predominant mediator of the development of the DDSP phenotype, and it receives signals from upstream kinases. Interestingly, PI3K is not required for signal transduction of damage responses in prostate fibroblasts, which occurs through Akt phosphorylation caused by activated p38 MAPK signaling. Conclusions: These studies establish that mTOR is a novel target for therapeutic intervention in the mitigation of resistance mechanisms derived from the tumor microenvironment following genotoxic cancer treatments. These studies suggest that mTOR inhibitors may have efficacy in augmenting tumor responses to ionizing radiation and/or chemotherapy.
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 1510. doi:1538-7445.AM2012-1510
Abstract 1519: Peroxisome proliferator-activated receptor ≤ promotes colonic inflammation and inflammation-associated tumorigenesis
Authors: Wang Dingzhi , Guo Lixia , Ning Wei , Wu Hong , Chaturved Rupesh , Wilson Keith , DuBois Raymond N. 
Published: August 2012

Abstract
Although epidemiologic and experimental evidence strongly indicates chronic inflammation as a risk factor for cancer, it remains unclear how chronic inflammation contributes carcinogenesis. Peroxisome proliferator-activated receptor ≤ (PPARδ) is one member of PPAR family that belongs to the nuclear hormone receptor superfamily and is also ligand-dependent transcription factor. Although PPARδ has been shown to be involved in chronic inflammation and the progression of hereditary and sporadic CRC, its role in inflammation-induced carcinogenesis is not defined. The aim of our present study was to determine whether PPARδ contributes to the pathogenesis of colonic inflammation and inflammation-associated carcinogenesis. Here we present genetic evidence demonstrating that deletion of PPARδ diminishes colonic inflammation accompanied with reducing infiltration of immune cells and the expression of pro-inflammatory chemokines and cytokines in a mouse model of colitis. These PPARδ-dependent chemokines are responsible for recruitment of leukocytes from the circulation to local inflammatory sites and the tumor microenvironment. Our results further reveal that activation of PPARδ induces COX-2 expression in colonic epithelial cells. Importantly, COX-2-derived PGE2 stimulates macrophages to produce pro-inflammatory chemokines and cytokines. More intriguingly, loss of PPARδ attenuated colonic chronic inflammation and colitis-associated adenoma growth via PGE2 signaling in two mouse models of colitis-associated tumorigenesis. Collectively, our results demonstrate that PPARδ promotes colonic chronic inflammation and colitis-associated tumor growth via a PGE2 signaling which mediates the crosstalk between tumor epithelial cells and macrophages. Our data further supports the notion that the existence of crosstalk between PPARδ and COX-2 signaling in CRC progression. These findings indicate that PPARδ plays a pivotal role in connecting colonic inflammation to cancer progression and may represent a potential therapeutic target for prevention or treatment of colorectal cancer.
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 1519. doi:1538-7445.AM2012-1519
Abstract 1520: Estrogen modulates angiogenic factors of thyroid tumor microenvironment
Authors: Rajoria Shilpi , George Andrea , Suriano Robert , Shin Edward J. , Geliebter Jan , Tiwari Raj K. 
Published: August 2012

Abstract
Thyroid cancer is the most common endocrine related cancer with the incidences occurring three to four times higher in women than in men, thus suggesting that estrogen plays a critical role in thyroid cancer progression. We have previously demonstrated that thyroid cancer cells express functionally active estrogen receptors (ER), ER-α and ER-α and that estrogen enhances the metastatic propensity of thyroid cancer cells by increased migration, adhesion and invasion, potentially mediated by enhanced secretion of matrix metalloproteinases (MMP), MMP-2 and MMP-9. However, to successfully grow and metastasize, thyroid cancer cells must initiate endothelial cell induced neo-vascularization such that adequate blood supply is maintained within the tumor. In an effort to define the interacting factors between endothelial cells and thyroid cancer epithelial cells, we developed an in vitro cell culture based system using three thyroid cancer cell lines (a papillary thyroid carcinoma cell line B-CPAP, and two follicular thyroid carcinoma cell lines, CGTH-W-1 and ML-1) and human umbilical vein endothelial cell (HUVECs). We observed that conditioned medium from estrogen treated thyroid cancer cells induced prolific tubulogenesis of endothelial cells which was abrogated in presence of the anti-estrogen, fulvestrant or neutralizing antibody to vascular endothelial growth factor (VEGF). We also observed that conditioned medium from thyroid cancer cells was able to induce migration of endothelial cells, again a phenomenon which was abrogated by fulvestrant and VEGF neutralizing antibodies. We further demonstrate that estrogen acts as a modulator of endothelial-epithelial cell interaction by modulating angiogenic factors that include VEGF and MMPs, which in turn induce mitogenic signaling and help promote and maintain cellular tumor heterogeneity. Estrogen modulated tumor modulating factors are viewed as novel therapeutic targets and provide evidence that the higher incidence of thyroid cancer in females is potentially attributed to the presence of a functional ER that mediates upregulation of pro-angiogenic factors and thus anti-estrogens can be potentially used to treat and/or prevent thyroid cancer.
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 1520. doi:1538-7445.AM2012-1520
Abstract 1527: CD44v9 involving in multiple myeloma cells adhesion to bone marrow stromal cell promotes bone erosion by augmenting the activation of HGF-receptor/cMet
Authors: Lee Chansu , Ahn Kwang-Sung , Ryu JIyeon , Park Soyoung , Jung Woo June , Park Juwon , Bae Eunkyung , Yoon Sung-Soo 
Published: August 2012

Abstract
The main aim of our study is to determine the significance of the stromal microenvironment in the malignant behavior of multiple myeloma cells. The stroma-derived growth factors/cytokines and hyaluronan act in autocrine/paracrine ways with their receptors, including receptor-tyrosine kinases and CD44 variants (CD44v), to potentiate and support multiple myeloma cell survival. In this study, we found that CD44s and CD44 variants were differentially expressed between fraction of CD138+ fraction and CD138- fraction. Expression levels of CD44v6, CD44v9, and CD44v10, respectively, correlated with bone erosion (p=0.029, p=0.013, p=0.032), suggesting that CD44 variant molecules are involved in multiple myeloma progression. Binding studies using CD44 isoform specific reagents showed that CD44v6 and CD44v9 were involved in binding to bone marrow stromal cells, but not to in vitro synthesized ECM. In 3D culture, CD44v6 and CD44v9-mediated plasma cell binding resulted in a significant induction of HGF secretion by bone marrow stromal cells. CD44v6 and CD44v9-mediated plasma cell binding significantly induces PI3K/Akt via activation the Src-kinase Lyn. In bone marrow serum of MM patients, the expression levels of IL-6, OPN, and hepatocyte growth factor (HGF), respectively, statistically correlated with bone erosion of MM patients (p=0.021, p=0.001, p=0.036). HGF derived from bone marrow stromal cells with multiple myeloma cells stimulates CD44 signaling via activation of HGF-receptor/cMet. Specific CD44 shRNA suppresses HGF-mediated CD44 signaling. Taken together, the role of CD44 variants in adhesion induced HGF- secretion may explain the previously observed correlation between CD44 variants expression and adverse prognosis in multiple myeloma.
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 1527. doi:1538-7445.AM2012-1527
Abstract 1537: Combined Tbet and IL-12 gene therapy elicits and recruits superior anti-tumor immunity in vivo
Authors: Taylor Jennifer L. , Qu Yanyan , Chen Lu , Lowe Devin B. , Storkus Walter J. 
Published: August 2012

Abstract
We have recently shown that intra-tumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective Type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Since IL-12 is a classical promoter of Type-1 immunity, the current study was undertaken to determine whether gene therapy using combined Tbet and IL-12 cDNA would yield improved anti-tumor efficacy based on the complementary/synergistic action of these biologic modifiers. Mice bearing established s.c. tumors injected with DC concomitantly expressing ectopic Tbet and IL-12 (i.e. DC.Tbet/IL12) displayed superior i.) rates of tumor rejection and extended overall survival, ii.) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and iii.) infiltration of CD8+ T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines. In established bilateral tumor models, i.t. delivery of DC.Tbet/IL12 into a single lesion led to slowed growth or regression at both tumor sites. Furthermore, DC.Tbet/IL12 pulsed with tumor antigen-derived peptides and injected as a therapy distal to the tumor site prevented tumor growth and activated robust antigen-specific Tc1 responses. These data support the translational use of combined Tbet and IL-12p70 gene therapy in the cancer setting. In order to target multiple gene pathways which should provide a more beneficial clinical outcome, we have begun combinational immunotherapy with DC.Tbet/IL12 and chemotherapeutic drugs targeting multiple receptor tyrosine kinases (i.e. sunitinib).
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 1537. doi:1538-7445.AM2012-1537
Abstract 1540: Inhibition of SDF production by brain tumor cells reduces brain tumor bed effect
Authors: Chiang Chi-Shiun , Ling Chi-Ming , Wang Shu-Chi , Hong Ji-Hong 
Published: August 2012

Abstract
Previous study on a murine prostate tumor model, TRAMP-C1, has shown that tumor transplants in preirradiated (pre-IR) tissues have longer growth delay and lower microvascular density (MVD) than in nonirradiated tissues, a phenomenon known as the tumor bed effect (TBE) that is associated with less responsive to salvage radiotherapy or chemotherapy and higher risk of metastasis. This study further demonstrates that a murine astrocytoma, ALTS1C1, grown from pre-IR brain tissues also have obvious TBE. This indicates that there is also a brain TBE that may affect the therapeutic efficacy of recurrent brain tumor after radiotherapy. Additional study shows that the inhibition of SDF expression in ALTS1C1 by specific siRNA reduces pre-IR-induced tumor growth delay and TAM association with hypoxia. The vessel formation mechanism is also altered into more mature form. This indicates that SDF production by brain tumor cells plays significant roles on the response of recurrent brain tumors after radiotherapy to salvage 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 1540. doi:1538-7445.AM2012-1540
Abstract 1555: Epigenetic modulation enhances the therapeutic effect of anti-IL13 receptor β2 antibody in human mesothelioma xenografts
Authors: Kato Kazunori , Takenouchi Makoto , Sakuragi Naoya , Yagita Hideo 
Published: August 2012

Abstract
Purpose: Interleukin-13 receptor β2 (IL13Rα2) is known as a cancer antigen and high expression of this receptor is found in various human cancers, such as glioma, renal cell carcinoma and prostate carcinoma. Immunotoxin or cytotoxin therapy for malignant glioma targeting IL13Rα2 has already been investigated in preclinical and clinical trials. Here, we have examined the constitutive surface expression and the epigenetic regulation of IL13Rα2 by human mesothelioma. We have also investigated the therapeutic effect of the DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5-aza-dC), and anti-IL13Rα2 monoclonal antibody on mesothelioma xenografts. Experimental Design: Cell surface expression of IL13Rα2 by various lung carcinomas was analyzed using flow cytometry. Therapeutic effects of anti-IL13Rα2 and 5-aza-dC were investigated using antibody-dependent cellular cytotoxicity and proliferation assays, and by monitoring the survival of mesothelioma-bearing mice. Results: We found that human malignant mesotheliomas expressed surface IL13Rα2 on their surface and that it was up-regulated by treatment with 5-aza-dC. This augmented expression of IL13Rα2 resulted in growth inhibition of the mesothelioma cells when co-cultured with anti-IL13Rα2 and effector cells, such as splenocytes and peritoneal exudate cells. The growth inhibition of mesothelioma cells was mediated by interferon-α that was only detected in the supernatant when effector cells were exposed to 5-aza-dC-treated tumors in the presence of anti-IL13Rα2. Compared with the control or either regimen alone, in vivo administration of anti-IL13Rα2 in combination with 5-aza-dC significantly prolonged the survival of mice with mesothelioma xenografts. Conclusion: These observations indicate a promising role for IL13Rα2 as a target for antibody treatment in malignant mesothelioma, and, in combination with epigenetic regulation by a DNA methylation inhibitor, suggest the potential for a novel strategy to enhance therapeutic potency.
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 1555. doi:1538-7445.AM2012-1555
Abstract 1565: Mesoporous silicon particle mediated dendritic cell based vaccine formulation showed stronger immunoresponse for the presentation of tumor antigens and adjuvant
Authors: Meraz Ismail M. , Gu Jianhua , Serda Rita 
Published: August 2012

Abstract
Dendritic cell (DC) based immunotherapy is being used for cancer therapy in various clinical trials. During evaluation of recent clinical studies, it became apparent that efficient DC-based immunotherapy is dependent on a number of factors, such as the mode of antigen presentation, maturation of DC, injection site, and vaccination dosing. Major limiting factors for DC-based vaccines are insufficient loading of antigens by DC and poor migratory capacity of DC to lymph nodes. Nanotechnology provides tools to load large payloads of antigens and adjuvants in particles for uptake by DC. Toll-like receptor (TLR) ligands have been proposed as vaccine adjuvants for boosting adaptive immunity in cancer therapy. TLR signaling induces DC activation that is characterized by enhanced expression of costimulatory molecules and increased secretion of cytokines necessary for activation and differentiation of naive T cells. In this study, we have used porous silicon (pSi) microparticles to create a novel vaccine. We have demonstrated that porous silicon particles can be decorated with TLR-ligands using lipopolysaccharide (LPS) or monophosphoryl lipid (MPL). This decorated particles are substrates for bone marrow-derived DC internalization, leading to cellular uptake and activation and enhanced migration of DC to lymph nodes. Confocal and scanning electron microscopy, as well as flow cytometry studies supported higher uptake of LPS and MPL conjugated particles as compared to unlabeled particles. TLR ligands induced morphological changes in GM-CSF-stimulated bone marrow cells during particle uptake consistent with classical DC dentron formation. Stimulated antigen presenting cells also expressed elevated levels of costimulatory (e.g. CD80, CD86) and major histocompatibility molecules (MHC), and secreted pro-inflammatory cytokines both in vitro and in vivo. Ex-vivo processed DC loaded with TLR ligand coated pSi showed enhanced migration to lymph node as compared with empty DC when injected mice subcutaneously. As expected, LPS conjugation to particles showed toxicity towards DC whereas MPL conjugated pSi showed little or no toxicity.
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 1565. doi:1538-7445.AM2012-1565
Abstract 1811: Antitumor activity of lapatinib in combination with the dual mTORC1/2 inhibitor INK-128 in breast tumors resistant to anti-HER2 therapy
Authors: Garcia-Garcia Celina , Ibrahim Yasir H. , Serra Violeta , Calvo Maria Teresa , Guzman Marta , Grueso Judit , Aura Claudia , Perez Jose , Jesen Katti , Liu Yi , Rommel Christian , Tabernero Josep , Baselga Jose , Scaltriti Maurizio 
Published: August 2012

Abstract
Purpose: The PI3K/Akt/mTOR pathway is an attractive target in HER2 positive breast cancer refractory to anti-HER2 therapy. The hypothesis is that suppression of this pathway results in sensitization to anti-HER2 agents. However, this combinatorial strategy has not been comprehensively tested in models of trastuzumab and lapatinib resistance. Experimental Design: We analyzed in vitro cell viability and induction of apoptosis in five different cell lines resistant to trastuzumab and lapatinib. Inhibition of HER2/HER3 phosphorylation, PI3K/Akt/mTOR and ERK signaling pathways was evaluated by western blot. Tumor growth inhibition following treatment with lapatinib, INK-128 or the combination of both agents was evaluated in three different animal models: two cell-based xenograft models refractory to both trastuzumab and lapatinib and a xenograft derived from a patient who relapsed to trastuzumab-based therapy. Results: The addition of lapatinib to INK-128 prevented both HER2 and HER3 phosphorylation induced by INK-128, resulting in inhibition of both PI3K/Akt/mTOR and ERK pathways. This dual blockade synergistically enhanced cell death in five different HER2 positive cell lines resistant to trastuzumab and lapatinib. In vivo, both cell line-based and patient-derived xenografts showed exquisite sensitivity to the antitumor activity of the combination of lapatinib and INK-128, causing durable tumor shrinkage in the absence of any sign of toxicity. Conclusions: The simultaneous blockade of PI3K/Akt/mTOR and ERK pathways achieved by combining lapatinib with INK-128 acts synergistically in inducing cell death and tumor regression in breast cancer refractory to anti-HER2 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 1811. doi:1538-7445.AM2012-1811