bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1517: The outcome of inhibition of stromal TGFβRII in pancreatic cancer is tumor cell-dependent
Authors: Ostapoff Katherine T. , Cenik Bercin K. , Carroll Kyla , Brekken Rolf A. 
Published: August 2012

Abstract
An elevated level of TGF-β is a negative prognostic indicator for patients with pancreatic ductal adenocarcinoma (PDAC). Despite this, the function of TGF-β signaling in tumor microenvironment stromal cells is unclear. We have studied how TGF-β-induced signaling in stromal cells (macrophages and fibroblasts) impacts human pancreatic cancer cell lines (Capan-1, MiaPaca-2, C5LM2 and Colo357) in vitro and in vivo. The TGFβRII activity in Raw 264.7 macrophages and 3T3 fibroblasts was inhibited with 2G8, a monoclonal rat anti-mouse TGFβRII IgG. Raw cells treated with 2G8 adopt a predominantly pro-inflammatory phenotype in vitro as documented by increased Hes1 and MCP-1 expression and inhibited tumor cell migration. Colony formation in soft agar was inhibited by conditioned media (CM) of Raw cells treated with 2G8 in all lines tested, except MiaPaca-2. Raw cell CM inhibited tumor cell proliferation in vitro compared to control media-treated tumor cells, but there were no significant differences between CM from Raw cells treated with 2G8 vs. a control IgG. CM from 3T3 cells treated with 2G8 also inhibited tumor cell migration and soft agar colony formation while control CM from 3T3 stimulated soft colony formation. MiaPaca-2, Capan-1 and Colo357 cells were orthotopically injected in SCID mice and were treated with saline or 2G8. 2G8 therapy differentially affected primary tumor size, such that inhibition of stromal TGFβRII stimulated the growth of MiaPaCa-2 tumors but inhibited the growth of Capan-1 and Colo357 primary tumors compared to treatment with a control IgG. Interestingly, 2G8 which only blocks mouse TGFβRII, suppressed metastasis in mice bearing MiaPaca-2, Capan-1 and Colo357 tumors. Furthermore, in isogenic cell lines derived from a 5 week old PDAC transgenic (p48-Cre; KrasG12D; Ink4alox/lox) mouse we also found a differential response to 2G8 therapy. Subcutaneous tumors that arose from clone MPLR 2D, were repressed by 2G8 therapy while subcutaneous tumors that arose from clone MPLR3B were stimulated by 2G8 therapy. The nature of differential response of the primary tumors and the mechanism of suppression of metastasis is under vigorous investigation. Our data thus far underscore the complexity and challenge of targeting the TGF-β pathway in pancreatic 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 1517. doi:1538-7445.AM2012-1517
Abstract 152: Nicotine inhibits the therapeutic effects of gemcitabine in pancreatic cancer cells in vitro and in a mouse xenograft model
Authors: Banerjee Jheelam , Al-Wadei Hussein A.N. , Schuller Hildegard M. 
Published: August 2012

Abstract
Pancreatic cancer is a leading cause of cancer deaths in developed countries. The nucleoside analog Gemcitabine, which induces apoptosis, is widely used for the therapy of pancreatic cancer. Smoking is an established risk factor for pancreatic cancer and nicotine replacement therapy often accompanies chemotherapy. Using the two human pancreatic cancer cell lines PANC-1 and BXPC-3 in vitro, our data show that low concentrations of nicotine significantly reduces the growth inhibiting effects of gemcitabine while also significantly inhibiting gemcitabine-induced apoptosis as indicated by determination of cleaved caspase-3 in immunoassays. Analysis of other signaling proteins is currently in progress. In a mouse xenograft model with BXPC-3 cells, a 1 micromolar concentration of nicotine in the drinking water significantly reduced the therapeutic response to gemcitabine while additionally reducing the induction of pro-apoptotic proteins and the inhibition of growth stimulating proteins by gemcitabine. Our data suggest that nicotine replacement therapy and possibly also the exposure to second hand smoke may negatively impact therapeutic outcomes of gemcitabine in pancreatic cancer patients. Nicotine addiction should be treated with non nicotine agents in such patients and exposure to tobacco smoke in any form should be avoided. Supported by grants RO1CA130888 and RO1CA042829 with the National Cancer Institute.
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 152. doi:1538-7445.AM2012-152
Abstract 1521: Expression of the tight junctions protein IGSF5 in the colorectal adenoma-carcinoma sequence
Authors: Briggs Alexandra , Rizvi Hira , Carothers Adelaide M. , Wang Jiping , Cho Nancy L. , Bertagnolli Monica M. 
Published: August 2012

Abstract
Patients with advanced adenomas are at high risk for the development of colorectal cancer, but predictors of disease progression remain elusive. Genome wide association study (GWAS) data from the Adenoma Prevention with Celecoxib (APC) Trial identified six germline single nucleotide polymorphisms (SNPs) that predicted advanced adenoma recurrence. These SNPs are located in tight linkage disequilibrium on chromosome 21 in or around the coding sequence for Immunoglobulin Superfamily Member 5 (IGSF5). This transmembrane protein localizes to tight junctions and modulates cell adhesion with its binding partner MAGI-1. We examined the expression of IGSF5 in normal colon tissue, adenomas and adenocarcinomas. By immunohistochemistry, IGSF5 was expressed in both crypt cells and stromal cells of normal human colon. With progression to adenoma and adenocarcinoma, IGSF5 expression became more membranous and diffuse in comparison to normal colon. Immunofluorescence histochemistry (IF) showed co-localization of IGSF5 with BMI-1 in normal colon crypt cells, indicating that intestinal stem cells express IGSF5. Pericryptal stromal cells expressing IGSF5 included both mesenchymal stem cells and hematopoietic stem cells, but not myofibroblasts, as indicated by IF colocalization with CD73 and CD34 but not αSMA, respectively. These results suggest that IGSF5 expression is altered in the progression from colorectal adenoma to carcinoma, and may exert its effects through stem cell modulation of intestinal homeostasis.
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 1521. doi:1538-7445.AM2012-1521
Abstract 1534: Hes1 regulates hypoxia induced chemoresistance of myeloma cells
Authors: Das Tuhin , Pisklakova Alexandra , Fei Zhaoliang , Nefedova Yulia 
Published: August 2012

Abstract
Bone marrow (BM) microenvironment plays a critical role in response of tumor cells to chemotherapeutic drugs. Hypoxia has been shown to contribute to pathogenesis not only solid but also hematological tumors. While normal BM environment is hypoxic, tumor growth is associated with increased hypoxia in BM niche. We have previously demonstrated that activation of Notch signaling could be one of the mechanisms responsible for survival of multiple myeloma (MM) cells from chemotherapeutic drugs. Here we investigated whether hypoxia could modulate Notch signaling and induce chemoresistance of MM cells. Three MM cell lines were treated with doxorubicin or melphalan in hypoxic (1% O2) or normoxic conditions. Using Annexin V binding assay we demonstrated that hypoxia induced chemoresistance in only one (H929) cell line studied. This effect was associated with significant up-regulation of expression of Notch target gene Hes1 and its protein level while Hes1 level was unchanged in other two MM cell lines. Inhibition of Hes1 with siRNA canceled the protective effect of hypoxia on MM cells. To further confirm the involvement of Notch pathway in regulation of drug sensitivity, Hes-1 was overexpressed in MM cells in normoxic condition using vector pIRES-AcGFP-Hes-1. MM cells with increased Hes1 level became less sensitive to chemotherapeutics as compared to cells transfected with control vector. Hes-1 is considered to be a Notch target gene. However, hypoxia did not affect Notch receptors expression level in MM cells. The effect of hypoxia on Hes1 was Notch-independent as was evident from Notch/CBF1 reporter assay. In addition, inhibition of Notch receptor cleavage with gamma-secretase inhibitor GSI-XII (Calbiochem) did not affect hypoxia induced MM cell chemoresistance. Up-regulation of Hes-1 was induced by HIF-1a as treatment of MM cells with hypoxia mimetic deferoxamine resulted in up-regulation of Hes1 and inhibition of HIF-1a with siRNA abrogated hypoxia-induced protection of MM cells. Thus, our study, for the first time, demonstrates that hypoxia could induce chemoresistance of MM cells through Notch-independent up-regulation of Hes-1. These results could be important not only for understanding the cancer biology but for designing therapeutic intervention in MM.
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 1534. doi:1538-7445.AM2012-1534
Abstract 1539: Antibody targeted CpG for the immunotherapy of solid tumors
Authors: Jang Julie K. , Hu Peisheng , Li Zhongjun , Khawli Leslie A. , Epstein Alan L. 
Published: August 2012

Abstract
A method is described to improve the therapeutic effects of unmethylated CpG oligodeoxynucleotides (ODNs) analogues, which can be used to stimulate the innate immune system for the treatment of cancer. The study is based on the generation of novel reagents that can be used to target tumors after linkage of CpG ODNs analogues to tumor-targeting monoclonal antibodies. This approach is novel in concept and may yield important information regarding the effectiveness of innate immunity in the treatment of cancer. CpG has been used primarily as an adjuvant injected locally at the site of interest or mixed with tumor vaccines. For systemic diseases such as cancer, however, the local administration of CpG would limit its potential to the site of injection. To address this, we have chemically linked active CpG motif analogues to chTNT-3, a monoclonal antibody which targets tumor necrosis, a site rich in tumor antigens. Our findings validate the usefulness of this novel approach and show that, compared to the parental antibody, the CpG immunoconjugate is able to target tumor and produce a 50% greater reduction in tumor growth. It is anticipated that the availability of antibody targeted CpG will enable research to optimize the effectiveness of this approach, especially when combined with other forms of immunotherapy, for the successful treatment of solid tumors. Additional studies using CpG motif analogues conjugated to rituximab (anti-CD20) and trastuzumab (anti-HER2/neu) are underway to demonstrate the full potential of this approach in tumors positive for these common biomarkers.
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 1539. doi:1538-7445.AM2012-1539
Abstract 154: [6]-Shogaol inhibits cell growth and induces apoptosis in non-small-cell lung cancer (NSCLC) cells by regulating multiple targets
Authors: Lee Mee-Hyun , Kim Myoung Ok , Oi Naomi , Bae Ki Beom , Huang Zunnan , Kang Soouk , Xie Hua , Lim Tae-Gyu , Bode Ann M. , Dong Zigang 
Published: August 2012

Abstract
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite substantial progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits the success of these therapies. NSCLC cells exhibit different EGFR mutations and EGFR has extensive cross-talk with other cell signaling pathways. Therefore, suppression of the inappropriate expression of multiple targets is considered to be a rational therapeutic and preventive strategy for the management of NSCLC. Our initial molecular-target oriented virtual screening revealed that the ingredients of ginger, including [6]-gingerol, [6]-shogaol and [6]-paradol appeared to be potential candidates for the prevention and therapy of NSCLC cells. Among the three compounds, [6]-shogaol showed the greatest inhibitory effect on growth and soft agar colony formation of NSCLC cells. [6]-Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, [6]-shogaol interacted with PI3-K and AKT and inhibited AKT kinase activity. Finally, [6]-shogaol increased the expression of p27, which is one of the target proteins in the AKT signaling pathway. The present results clearly indicate that [6]-shogaol exerted a strong anti-cancer effect and can be regarded as useful tool for the treatment of NSCLC.
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 154. doi:1538-7445.AM2012-154
Abstract 1544: Combined oncolytic virotherapy and immunotherapy for malignant mesothelioma
Authors: Guo Z. Sheng , Zhou Jingjiao , O'Malley Mark E. , Sathaiah Magesh , Bartlett David L. 
Published: August 2012

Abstract
Introduction. Oncolytic viruses have therapeutic potential in cancer by selectively replicating within malignant cells and/or other cells in the tumor tissues, causing cell death. Vaccinia virus (VACV) with deletion of viral genes encoding for thymidine kinase and vaccinia growth factor and armed with a chemokine gene encoding CCL5 (vvDD-CCL5) has been previously shown to be safe and efficacious in a murine colon cancer model (Li J. et al., Mol Ther., 19: 650-7; 2011). Here we explored combination therapy with the use of this armed oncolytic virus and immunotherapy in a murine malignant mesothelioma model in syngeneic BALB/c mice. Methods. The viral replication and oncolysis was examined in murine AB12 mesothelioma cancer cells in vitro, and the combination of oncolytic virus, IL-2 and anti-CD25 and anti-CTLA4 antibodies, was investigated in vivo to treat a murine model of peritoneal malignant mesothelioma (PMM) derived from AB12 cells in BALB/c mice. Results. In vitro, vvCCL5 and its parental virus vvDD replicate well in AB12 cancer cells and lead to efficient cytotoxicity in these cancer cells. In vivo biodistribution analysis indicated that both viruses displayed highly tumor selective replication; however, vvDD-CCL5 replicated to a greater extent and displayed increased persistence in the tumor tissue. As a result, vvDD-CCL5 was more efficient than vvDD, working in a viral dose-dependent manner and leading to increased survival of tumor-bearing mice. Combination therapy of virus with antibodies against CD25 and CTLA4 and IL-2 was investigated. Clearly, this has been the best strategy to treat AB12 PMM, achieving the best long-term survival of mice. We are currently investigating its cellular and molecular mechanisms by this combination leading to tumor regression and long-term survival of mice. Conclusions: The chemokine gene-armed oncolytic virus (vvDD-CCL5) is effective in a PMM tumor model. The combination of this virus with an immunologic regimen of Treg depletion and IL-2 treatment has been demonstrated to be highly efficacious for PMM. Further understanding of its cellular and molecular mechanisms of this treatment strategy will facilitate the optimization of combined therapeutic regimens for PMM.
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 1544. doi:1538-7445.AM2012-1544
Abstract 1546: Combined direct intratumoral adenoviral delivery and production of Rheoswitch®-regulated IL-12 and IFNα enhances antitumor activity in lung and breast cancer models
Authors: Murugesan Selva , Chan Tim , Reed Charles , Bharathan Mini , Connelly Sheila , Fogler William E. , Youssoufian Hagop , Herberman Ron 
Published: August 2012

Abstract
Current cancer immunotherapies have provided limited success in the clinic and innovative strategies are required to further enhance the effectiveness of an anti-tumor immune response.This study assessed anti-tumor activity utilizing intratumoral (i.t.) administration of adenovirus (Ad) with the novel Rheoswitch Therapeutic System®(RTS®), an inducible promoter system, for regulated expression of murine IL-12 or IFNα. Oral administration of a small molecule activator ligand (AL), INXN-1001, regulates the expression of IL-12 in Ad-RTS-mIL-12 and IFNα in Ad-RTS-mIFNα. The regulated expression and therapeutic benefit of IL-12 and IFNα from i.t. administered Ad-RTS-mIL-12 and Ad-RTS-mIFNα, either alone or in combination, was examined in syngeneic Lewis lung carcinoma (LLC) and syngeneic mammary carcinoma (4T1) models. In the LLC model, daily treatment with oral AL alone (administered in feed at 1000 ppm, representing a daily dose of ∼225 mg/kg/day) or i.t. cytokine gene therapy in the absence of AL did not result in significant inhibition of tumor growth compared to control, untreated tumors. In contrast, i.t. injection with 1010 vp Ad-RTS-mIL-12 or Ad-RTS-mIFNα and daily oral AL led to significant tumor growth inhibition by day 25 (72 and 71%, respectively; p&lt;0.05). Notably, combined treatment of the LLC tumors with Ad-RTS-mIL-12 and Ad-RTS-mIFNα with oral AL resulted in significant anti-tumor effect compared to either treatment alone (97% growth inhibition; p&lt;0.05) without overt toxicity as assessed by no change in body weight. In the 4T1 model, i.t. treatment with 1010 vp of Ad-RTS-mIL-12 plus AL or Ad-RTS-mIFNα plus AL led to 58 and 53% inhibition of tumor growth compared to control untreated tumors by day 34 (p&lt;0.05). Notably, concomitant treatment with both Ad-RTS-mIL-12 plus AL and Ad-RTS-mIFNα plus AL resulted in enhanced anti-tumor activity with 80% growth inhibition. These data indicate that the combined treatment strategy using RTS-regulated IL-12 and IFNα in Ad vectors concomitant with AL induces effective therapeutic activity against aggressive murine tumors. Future studies will investigate the mechanism by which both IL-12 and IFNα exert their anti-tumor effect in the above tumor models.
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 1546. doi:1538-7445.AM2012-1546
Abstract 1548: Ultraviolet B-induced platelet-activating factor receptor agonists mediate augmentation of melanoma tumor growth via regulatory T cells: Implication of systemic immunosuppression
Authors: Sahu Ravi P. , Konger Raymond L. , Touloukian Christopher E. , Travers Jeffrey B. 
Published: August 2012

Abstract
Ultraviolet B (UVB)-irradiation to human or mouse skin generates Platelet-activating factor (PAF) and novel oxidatively-modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma progression. As our studies demonstrated that B16F10 tumors do not express functional PAF-Rs, retroviral-mediated transduction of the PAF-R was used to create PAF-R-positive B16F10 melanoma tumor cells. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell, PAF-R-expression as UVB or the PAF-R agonist, carbamoyl- PAF (CPAF), both promote B16F10 tumor growth in wild-type mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in PAF-R deficient (Pafr -/-) mice. Systemic antioxidant treatment ameliorated UVB-mediated augmentation of tumor growth, indicating involvement of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice, or depletion of CD25-positive cells (suggestive of FoxP3 directed regulatory T cells) in FoxP3EGFP transgenic mice block UVB/CPAF-induced tumor growth, supporting a requirement for IL-10 and regulatory T cells (Tregs) in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression. These studies describe a previously unrecognized mechanism by which melanoma tumor cells can escape antitumor immunity. Inasmuch as other pro-oxidative stressors could potentially generate PAF-R agonists, this pathway could have clinical relevance in terms of devising better strategy for melanoma immunotherapy.
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 1548. doi:1538-7445.AM2012-1548
Abstract 1554: Rosiglitazone and Gemcitabine combination therapy reduces immune suppression and modulates T cell populations in pancreatic cancer
Authors: Bunt Stephanie K. , Mohr Ashley M. , Bailey Jennifer M. , Grandgenett Paul M. , Hollingsworth Michael A. 
Published: August 2012

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer mortality with a dismal 2-5% 5-year survival rate. Monotherapy with Gemcitabine has limited success, highlighting the need for additional therapies that enhance the efficacy of current treatments. We evaluated the combination of Gemcitabine and Rosiglitazone Maleate, an FDA-approved drug for the treatment of type II diabetes, in an immunocompetent transplantable mouse model of pancreatic cancer. Tumor progression, survival and metastases were evaluated in mice with subcutaneous or orthotopic pancreatic tumors treated with Pioglitazone, Rosiglitazone, Gemcitabine or combinations of these. We characterized the impact of high dose Rosiglitazone and Gemcitabine therapy on immune suppressive mediators, including MDSC and T regulatory cells, and on modulation of peripheral and intra-tumoral T cell populations. Combinations of Rosiglitazone and Gemcitabine significantly reduced tumor progression and metastases, enhanced apoptosis, and significantly extended overall survival compared to Gemcitabine alone. Rosiglitazone altered tumor-associated immune suppressive mediators by limiting early MDSC accumulation and intra-tumoral T regulatory cells. Combination therapy with Rosiglitazone and Gemcitabine modulated T cell populations by enhancing circulating CD8+ T cells and intra-tumoral CD4+ and CD8+ T cells while limiting T regulatory cells. The results suggest that Rosiglitazone, in combination with Gemcitabine, decreases immune suppressive mechanisms in immunocompetent animals and provide pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic 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 1554. doi:1538-7445.AM2012-1554