bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 709: Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells
Authors: Bachmeier Beatrice E. , Killian Peter H. , Kronski Emanuel , Efferth Thomas 
Published: June 2012

Abstract
Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate (ART), clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of ART in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, ART induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, ART was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP 1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of ART in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that ART induces resistance in highly metastatic breast tumors.
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 709. doi:10.1158/1538-7445.AM2011-709
Abstract 721: Putative molecular mechanism contributing AZD6244 resistance in lung cancer
Authors: Yamaguchi Hirohito , Hsu Jennifer , Ko How-Wen , Wang Ying-Nai , Chang Shih-Shin , Hung Mien-Chie 
Published: June 2012

Abstract
The K-ras proto-oncogene is mutated in about 10-30% of non-small cell lung cancer, and these mutations are responsible for constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway, Raf/MEK/ERK. Therefore, several MEK inhibitors are currently under clinical trials to target K-Ras mutant lung cancer. AZD6244 (ARRY-142886) is an orally active and selective inhibitor that specifically targets MEK. We investigated the effect of AZD6244 on NSCLC cell lines to further understand the detailed molecular mechanism contributing to the sensitivity to this drug. Interestingly, two NSCLC cell lines, which have previously been reported as AZD6244-sensitive, exhibited a differential response to MEK inhibition by AZD6244. Specifically, long-term treatment by this drug eventually induced resistance in one of the two cell lines. We analyzed protein expression profile of the Bcl-2 family members which we hypothesized might play a role in the resistance to AZD6244 treatment. We found that while Bim appears to be stabilized in both apoptosis-resistant and -sensitive lung cancer cells, MCl-1 expression is increased in apoptosis-resistant lung cancer cells, suggesting that the increase in anti-apoptotic MCl-1 expression likely contributes to resistance under long-term AZD6244 treatment.
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 721. doi:10.1158/1538-7445.AM2011-721
Abstract 728: Molecular mechanisms of resistance to anti-IGF-1R therapies in Ewing's sarcoma
Authors: Garofalo Cecilia , Manara Maria Cristina , Marino Maria Teresa , Lollini Pier Luigi , Picci Piero , Scotlandi Katia 
Published: June 2012

Abstract
IGF-1R represents a promising therapeutic target, particularly in sarcomas. Identification of patient selection criteria and understanding the potential mechanisms involved in development of resistance will be crucial for an appropriate and successful design of clinical trials.
Here we evaluated efficacy of the anti-IGF-IR monoclonal antibody (HAb) AVE1642, in a panel of sarcoma cell lines and we developed a model of resistance to the anti-IGF-1R human antibody AVE1642 or to the small tyrosine kinase inhibitor (TKI) NVP-AEW541 starting from two highly sensitive Ewing's sarcoma cell lines to identify indicators of intrinsic and adaptive resistance to anti-IGF1R therapies.
Cells made resistant to AVE1642 showed same growth ability either in monolayer and in anchorage-independent condition respect to sensitive cells. Notably, resistant cells retained the same level of sensitivity to doxorubicin, vincristine, and ifosfamide as the parental cell lines. Annotation analysis highlighted that the insulin pathway seems to be significant in resistant cells. In fact, these cells showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Molecular characterization demonstrate that enhanced IR-A formation and IGF-II production are heavily involved in native and acquired resistance to IGF targeted therapies. This finding was extended to cells resistant to the small tyrosine kinase inhibitor NVP-AEW541.
We also show that tumors with low IGF-1R:IR-A ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells.
Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF1R therapies and provide evidences supporting IR-A as an important target in sarcoma therapy. Future trials with these highly selective drugs should involve preselection of patients with tumors that express low levels of IR-A and IGF-2.
Studies are supported by grants from the Italian Association for Cancer Research, the Italian Ministry of Health, the Italian Ministry of Research and Instruction and the EU project Eurobonet.
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 728. doi:10.1158/1538-7445.AM2011-728
Abstract 733: A therapeutic opportunity in melanoma: Targeting CXCR1/2-dependent signaling attenuates therapy resistance
Authors: Wu Sheng , Varney Michelle L. , Singh Seema , Singh Rakesh K. 
Published: June 2012

Abstract
Advanced melanoma is one of the most intractable tumors, due to its insensitivity to all current treatment. Systemic chemotherapy is still considered the mainstay of treatment for advanced melanoma with limited survival impact. Failure of most agents is attributed to development of therapy resistance. Our previous findings demonstrate that CXCL-8 is a critical mediator in tumor growth, invasion, and angiogenesis. Two high affinity receptors for CXCL-8, CXCR1 and CXCR2, are differentially expressed on melanoma and endothelial cells. Based on these observations, we hypothesize that targeting CXCR1/2-dependent signaling will attenuate chemotherapy resistance and will synergistically enhance chemotherapeutic response for malignant melanoma. We used human melanoma cell lines A375P (low metastatic) and A375SM (highly metastatic), which express low and high levels of CXCL-8 respectively. First, we evaluated the role of CXCR1/2 ligands in chemo-resistance. CXCL-1 and -8 mRNA and protein expression was analyzed by quantitative realtime PCR and enzyme-linked immunosorbant assay, following treatment of dacarbazine and temozolomide. A significant increase in the CXCL-1 and -8 levels was observed in A375P and A375SM cells which was dependent on concentration and duration of chemotherapeutic treatment. In order to test whether blocking CXCR1/2 expression using genetic knock-down modulates chemotherapeutic responses, we used A375SM cells expressing different levels of CXCR1 and CXCR2. Our data suggest that knockdown of CXCR1 significantly enhanced the cytotoxic effect of dacarbazine in vitro. However, we did not observe a similar response in melanoma cells knocked down for CXCR2. Taken together, our preliminary data demonstrate that melanoma cells that survive chemotherapy express higher levels of CXCR1/2 ligands and targeting the CXCR1/2-dependent pathway might be a potential therapeutic approach to be combined with chemotherapy in advanced melanoma.
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 733. doi:10.1158/1538-7445.AM2011-733
Abstract 750: Identification of tumor antigens in transgenic mouse model as vaccine targets for the prevention of human breast cancer
Authors: Mao Jianning , Wu Mei , Gad Ekram , Lu Hailing , Disis Mary 
Published: June 2012

Abstract
The development of a vaccine to prevent breast cancer would be facilitated if tumor antigens were identified which were associated with the initiation of the malignant transformation. Transgenic mouse models have been proven to demonstrate a similar antigenic repertoire as that seen in breast cancer patients, therefore, we propose to use these models to identify tumor antigens as vaccine targets for breast cancer prevention. We have chosen two mouse models: TgMMTV-neu and TgC3(1)-Tag for study. TgMMTV-neu mouse has a genotype similar to luminal breast cancer and the TgC3(1)-Tag model reflects a basal phenotype of breast cancer. We identified potential vaccine candidate antigens in one of two ways; (1) determining which proteins expressed by the cancer are immunogenic very early in the malignant process by screening pre-diagnostic sera for immunogenicity against tumor cDNA libraries, and (2) injecting parental animals with a syngeneic tumor cell line resulting in “tumor rejection” which we have shown previously is mediated by T cells. To date, we have identified nine pre-diagnostic tumor antigens in TgMMTV-neu mouse; Rpl5, TNFaip3/A20, Pdhx, Otud6b, Stk39, Zfp238, Dnajc10, Lgals8 and Vps35. Moreover, we have identified four rejection antigens in TgC3(1)-Tag mouse; Ddx21, Sfrs11, Edh1 and Tdg. We have initiated vaccination experiments to examine the anti-tumor effect of vaccination with plasmids encoding these antigens. We found that vaccination targeting Ddx21, Dnajc10, and Pdhx mediated tumor growth inhibition in implant models compared with a control group (p&lt;0.01). Our preliminary studies also demonstrate that several of the proteins are immunogenic in humans and we have identified putative promiscuous class II epitopes suitable for screening human PBMC for T cells specific to these proteins.
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 750. doi:10.1158/1538-7445.AM2011-750
Abstract 771: Therapy of spontaneous primary breast tumors in neu-N transgenic mice by adoptive transfer of vaccine-primed LN T cells also induces a humoral response
Authors: Wang Li-Xin , Plautz Gregory E. 
Published: June 2012

Abstract
To investigate factors which regulate T-cell mediated therapy of primary breast tumors in situ, we utilized neu-N transgenic mice. These neu-tolerant mice develop spontaneous breast tumors, several of which we have established as aggressive transplantable tumors and selected stem-like progenitor cells in vitro. We vaccinated neu-N mice with irradiated neupos breast cancer progenitor cells to prime T cells in draining LNs. We purified a minor subset (5% to 10%) of LN cells with a CD62Llow CD4+ or CD8+ phenotype representing recently activated effector cells. CD4 and CD8 subsets were separately activated in vitro with anti-CD3/IL-2/IL-7 for two stimulation cycles to induce 200-fold numerical expansion. Hosts bearing spontaneous primary breast tumors average 80 mm2 were treated with 35 × 106 of each CD4+ and CD8+ subsets. Even though the neu-tolerant hosts did not receive lymphodepletion prior to T cell transfer, the T cells significantly delayed tumor growth compared with untreated control mice (n=4 per group, p=0.037). This extends our previous work showing effective T cell therapy of inoculated lung metastases to primary in situ neu-N breast tumors. Neu is a transmembrane tumor antigen with shared expression between vaccine cells and spontaneous tumors that could contribute to the anti-tumor response. We also searched for evidence of response against other cross-reactive antigens. Interestingly, treated mice developed a humoral response and post-treatment serum IgG bound to neuneg variant tumor cells as well as neupos cell lines whereas pre-treatment serum was non-reactive. The development of an IgG serologic response following effective T cell-mediated therapy (in the absence of co-transferred B cells) indicates that transferred CD4+ T cells provided cognate helper function and immunoglobulin class switch signals to B cells and reversed tolerance to neu as well as other shared tumor antigens.
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 771. doi:10.1158/1538-7445.AM2011-771
Abstract 776: Therapeutic immunity against melanoma by IL-12 cDNA electroporation: a possible therapeutic mechanism
Authors: Sin Jeong-Im , Ryoo Hun Mo 
Published: June 2012

Abstract
We observed that large-established melanoma was eradicated by intratumoral (IT)-electroporation (EP) of IL-12 cDNA in an animal model. In this study, we explored the mechanism(s) as to how this tumor eradication is mediated in vivo and evaluated if long-term memory responses to parental tumor cell re-challenge can be induced. Melanoma (B16) cells were subcutaneously inoculated. When tumor reached 6-8 mm in mean diameter, 50 μg of IL-12 cDNA was intratumorally injected and electroporated using Cellectra® of VGXI at 0.2A for 4 sec. To further determine the antitumor mechanism(s), IT-EP was performed in tumor-bearing wild type, IFN-γ knockout (KO), and perforin KO animals. Furthermore, immune cell infiltration was measured by histological analysis. In vitro and in vivo immune cell subset depletion assay was also performed to see an involvement of T and NK cell populations in tumor Ag-specific IFN-γ production and tumor control. IT-EP of IL-12 cDNA resulted in eradicating tumors established on the skin without any significant levels of long-term antitumor memory immunity. This effect required mainly CD8+ and to a lesser degree CD4+ T cells, but not NK cells. Both IFN-γ KO animal studies and IT-EP assay of IFN-γ cDNA confirmed that IFN-γ was indirectly involved in melanoma control. Furthermore, perforin was found to be essential for the tumor-eradicating activity. However, B16 melanoma cells expressed Fas, but failed to exhibit Fas-mediated cell lysis, suggesting that perforin/granzyme B-mediated killing pathway is associated with CD8+ T cell-mediated melanoma control. Taken together, these studies show that IT-EP of IL-12 cDNA is an important approach to control melanoma on the skin and this antitumor effect is mediated mainly by CD8+ T cells (as a killer T cell) through perforin/granzyme B-mediated killing pathway. This study also suggests that additional approaches are needed to induce long-term antitumor memory responses.
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 776. doi:10.1158/1538-7445.AM2011-776
Abstract 78: Epigenetic regulation of the metastatic progression of non-small cell lung cancer by the histone H3K9 methyltransferase SETDB1
Authors: Tzeng Tsai-Yu 
Published: June 2012

Abstract
Aberrant histone methylation is contributes to tumor development and progression by histone methyltransferase. SETDB1 is an authentic H3K9 methyltransferase that contributes to the epigenetic silencing of target genes in cancer cells, but the role of SETDB1 function in mediating tumor metastasis has not been reported. We show here that H3K9Me2 and SETDB1 are down-regulated in metastatic lung cancer cell lines. Ectopic expression of SETDB1 in highly invasive lung cancer cells suppressed cancer cell migration, invasion and filopodia formation. In contrast, knockdown of endogenous SETDB1 in non-invasive lung cancer cells by RNA interference increases cell migration and invasion in vitro. Mechanistic investigations suggested that SETDB1 is specifically down-regulated by miR-29b in metastatic lung cancer cells. Ectopic miR-29b expression in non-invasion lung cancer cells increases cell invasion ability. These results indicate that SETDB1 contributes to the repressive role and concomitant dysregulation of epigenetic pathways in 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 78. doi:10.1158/1538-7445.AM2011-78
Abstract 784: Prevalence, phenotype and prognostic significance of IL-17-producing cells infiltratinghuman colorectal cancers
Authors: Amicarella Francesca , Zlobec Inti , Muraro Manuele Giuseppe , Han Junyi , Huber Xaver , Zuber Markus , Adamina Michel , Oertli Daniel , Lugli Alessandro , Terracciano Luigi , Zajac Paul , Spagnoli Giulio Cesare , Iezzi Giandomenica 
Published: June 2012

Abstract
Background: Lymphocytic infiltration is known to be associated with a favourable prognosis in human colorectal cancer (CRC). In particular, the presence of CD8+ T cells and, unexpectedly, of Foxp3+ regulatory T cells, has been found to be associated with improved patient survival. Recent evidence suggests that IL-17 and T helper (Th) 17 cells might also have an impact on anti-tumour immune responses. We have investigated prevalence, phenotype and prognostic significance of IL-17-producing cells in human CRC.
Material and Methods: IL-17 expression was evaluated by immunohistochemistry on a tissue micro-array (TMA) including 1420 cases of primary CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC tissues by quantitative PCR.
Finally, in order to characterize the phenotype of IL-17-positive cells, expression of IL-17, in combination with that of specific surface molecules, was analyzed on freshly excised CRC specimens by flow cytometry.
Results: Frequencies of IL-17-producing cells, as well as IL-17 gene expression levels were significantly increased in tumour tissues as compared to autologous normal mucosa. IL-17-producing cells isolated from clinical specimens were exclusively comprised within the lymphocyte population and expressed CD4, but not CD8, and surprisingly, Foxp3 molecules. Accordingly, mRNA levels of genes encoding for cytokines favouring IL-17 acquisition by Foxp3+ T cells, including IL-6, IL-1beta, TGF-beta and IL-23, were found more elevated in CRC tissues as comparing to corresponding healthy mucosa.
High infiltration by IL-17 producing cells significantly correlated with low T and N stages, and, most importantly, with prolonged survival time in mismatch repair (MMR)- proficient, but not-deficient CRC. Moreover, the simultaneous CRC-infiltration by IL-17+ and Foxp3+ cells was significantly associated with improved survival in both MMR-proficient and -deficient tumours.
Conclusions: Our data suggest that IL-17 produced by tumour-infiltrating either CD4+ or Foxp3+ cells may promote a benign clinical outcome in CRC.
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 784. doi:10.1158/1538-7445.AM2011-784
Abstract 811: Co-inhibition of cyclooxygenase-2 and inducible nitric oxide synthase prevents N-nitrosomethylbenzylamine-induced esophageal squamous cell carcinoma in rats
Authors: Guan Huaji , Yan Fei , Wang Yufen , Battista Carter , Huang Xin , Stoner Gary D. , Nines Ronald G. , Edmonds Alexandria M. , Chen Tong 
Published: June 2012

Abstract
Hyperactivation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been observed separately in esophageal squamous cell carcinoma (ESCC) in rats that is induced by N-nitrosomethylbenzylamine (NMBA), a powerful carcinogen found in some human diets. In approach to discover new prevention strategies for ESCC, celecoxib and S,S′-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), selective inhibitors respectively to COX-2 and iNOS, were evaluated in the NMBA-rat preclinical esophageal cancer model. F344 rats were treated with NMBA (0.30mg/kg b.w.) three times per week for five weeks. Seventy-two hours after the last NMBA treatment, rats were fed with control diet with or without different doses of celecoxib and PBIT. At week 35, rats were sacrificed and esophageal tumors were counted. Celecoxib (1000 ppm) or PBIT (100 ppm) alone, and a combination treatment with celecoxib (500 ppm) and PBIT (50 ppm), significantly decreased the NMBA-induced tumor multiplicity (from 4.73 ± 0.45 to 2.00 ± 0.25, 1.89 ± 0.23, and 1.61 ± 0.27, respectively), which were accompanied by the inhibition of transcription, translation and kinase activity of both COX-2 and iNOS in all these treatments. By using this COX-2/iNOS co-inhibition strategy, celecoxib/PBIT combination inhibited cancerous esophagus cell proliferation by immunohistochemistry staining of PCNA, and decreased c-Myc expression in NMBA-induced papillomas by Western blot analysis. In addition, the histopathological examination of rat esophagus showed that celecoxib/PBIT combination significantly prevented NMBA-induced tumor transformation (from 8.373% to 1.765%). In conclusion, our results indicated that co-inhibition of COX-2 and iNOS by Celecoxib/PBIT combination prevented NMBA-induced ESCC in rats, which represents a new means of esophageal cancer prevention. (Supported by NIH/NCI RO1 CA131073-01A1).
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 811. doi:10.1158/1538-7445.AM2011-811