bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1465: Prognostic significance of stem cell and EMT phenotype in Circulating Tumor Cells.
Authors: Strati Areti D. , Georgoulias Vasilis , Lianidou Evi 
Published: August 2014

Abstract
Background: Circulating tumor cells (CTCs) are associated with prognosis and can be used as a liquid biopsy for repeated follow up examinations. The subpopulation of CTCs that successfully establish distant metastases share EMT and stemness features. These cells have been found to be associated with resistance to anti-cancer therapies and treatment failure.
Patients and methods: Peripheral blood (20 mL in EDTA) was obtained and after density gradient centrifugation, immunomagnetic Ber-EP4 coated capture beads were used to enrich for epithelial cells from 102 patients with early breast cancer and 23 patients with verified metastasis. Messenger RNA was isolated from enriched epithelial cells using oligo (dT)25 coated magnetic beads. After cDNA synthesis the expression of CK-19, MAGE-A3, HER-2, PBGD and CD24, CD44, ALDH1, HPRT was tested, using two different quadruplex RT-qPCR assays. Moreover we performed RT-qPCR for the expression of TWIST1, hMammaglobin and hTERT α+β+.
Results: The presence of circulating tumor cells was evaluated using CK-19, MAGE-A3, HER-2, hTERT α+β+, and mammaglobin gene transcripts. In 102 operable breast cancer patients 31 patients (30.4%) were found positive for the presence of CTCs. CTC biomarkers were significantly correlated with lymph nodes (P=0.032). In the CTC+ group, 10 patients (32.3%) were positive for TWIST1 and 16 (51.6%) were positive for CD44+/CD24-/low and ALDH1+ cell phenotype. We found a significant correlation between HER2 negative tumors with TWIST1 expression (P=0.027) and Stem Cell phenotype (P=0.012). The detection of both EMT and Stem Cell characteristics was associated with shorter disease-free survival (P=0.024). In the CTC positive group of patients with verified metastasis (39.1%) 1 patient (11.1%) was positive for TWIST1 and 4 (44.4%) were positive for CD44+/CD24-/low and ALDH1+ cell phenotype. The detection of CK19+, Stem Cell and Stem Cell and/or EMT phenotype was associated with shorter overall-free survival (P=0.036, P=0.001 and P=0.002).
Discussion: CTCs in breast cancer patients share both stem cell and/or EMT phenotype. The detection and molecular characterization of CTCs with an EMT or stem cell-like characteristics could be a powerful diagnostic tool for the determination of prognosis and designing new therapeutic drugs for the elimination of minimal residual disease.
Citation Format: Areti D. Strati, Vasilis Georgoulias, Evi Lianidou. Prognostic significance of stem cell and EMT phenotype in Circulating Tumor Cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1465. doi:10.1158/1538-7445.AM2013-1465
Abstract 1489: The T-box transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to chemotherapy and radiation.
Authors: Huang Bruce K. , Cohen Joseph , Fernando Romaine I. , Hamilton Duane H. , Litzinger Mary T. , Hodge James W. , Palena Claudia M. 
Published: August 2014

Abstract
The T-box transcription factor Brachyury, a molecule frequently detected in human cancers but seldom found in normal adult tissue, has recently been proposed as a significant determinant of the epithelial-mesenchymal transition (EMT) in human carcinomas. In the current investigation, we present data demonstrating that in three different human lung carcinoma models, expression of Brachyury is associated with a mesenchymal phenotype. Additionally, elevated Brachyury expression is shown to strongly correlate with increased in vitro resistance to cytotoxic therapies, such as chemotherapy and radiation. Further investigation showed that chemotherapy treatment in vitro selected tumor cells that were high in Brachyury, and that the degree of resistance to therapy was comparable to the level of Brachyury expression. We also demonstrate that in vitro and in vivo, human lung carcinoma cells with greater levels of Brachyury divide at slower rates than those with lower levels of Brachyury, a phenomenon associated with marked downregulation of cyclin D1, phosphorylated Rb (pRb), and CDKN1A (p21). ChIP and luciferase resporter assays revealed that Brachyury represses p21 expression in carcinoma cells by directly binding to a half T-box consensus site located within the promoter region of the p21 gene, indicating a potential mechanism for the observed therapy resistance associated with Brachyury expression. Finally, we observed that in vivo treatment of tumor xenografts with chemotherapy resulted in the selective growth of resistant tumors that were high in Brachyury. Altogether, these results suggest that in addition to being a driver of EMT, Brachyury expression may attenuate cell cycle progression, and enable tumor cells to become less susceptible to chemotherapy and radiation in human carcinomas.
Citation Format: Bruce K. Huang, Joseph Cohen, Romaine I. Fernando, Duane H. Hamilton, Mary T. Litzinger, James W. Hodge, Claudia M. Palena. The T-box transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to chemotherapy and radiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1489. doi:10.1158/1538-7445.AM2013-1489
Abstract 1507: Iron upregulates HLA-G mRNA expression of the human MCF-7 breast cancer cell line.
Authors: Head Jonathan F. , Jiang Xian P. , Elliott Robert L. 
Published: August 2014

Abstract
HLA-G is a nonclassical MHC Class I molecule that protects the fetus from the maternal immune system, and it also plays a role in immune evasion of cancer. Previously we have shown that iron can suppress the cytolytic function of natural killer cells to human breast cancer cell lines. We have found that breast cancer cells over express HLA-G mRNA and proteins in both cell lines and breast carcinomas. In order to determine if iron concentration affects HLA-G expression, we cultured the human breast cancer cell line MCF-7 in media with 100 mM, 400 mM, and 1600 mM of iron for 24 hours. We used RT-PCR to examine HLA-G mRNA expression of the MCF-7 cells. The PCR primers were designed so that they could detect all alternatively spliced HLA-G mRNA isoforms, 1000 bp (HLA-G1 and HLA-G5), 600 bp (HLA-G2 and HLA-G4), and 300 bp (HLA-G3). RT-PCR showed that the MCF-7 cells cultured with control medium only had one band of 300 bp mRNA expression. However, the MCF-7 cells cultured in medium containing 100 mM, 400 mM, and 1600 mM of iron had three bands of 300 bp, 600 bp, and 1000 bp HLA-G mRNA expression. Moreover, the intensity of the 300 bp band from the iron-treated MCF-7 cells is significantly higher than the cells cultured with control medium. In summary, iron upregulates the HLA-G mRNA expression of MCF-7 cells, and this probably contributes to cancer immunosuppression and to the cytolytic dysfunction of natural killer cells.
Citation Format: Jonathan F. Head, Xian P. Jiang, Robert L. Elliott. Iron upregulates HLA-G mRNA expression of the human MCF-7 breast cancer cell line. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1507. doi:10.1158/1538-7445.AM2013-1507
Abstract 1511: Stromal gene signature regulated by TGFβ signaling predicts poor clinical outcome in ovarian cancer .
Authors: Cheon Dong-Joo , Tong Yunguang , Sim Myung-Shin , Cui Xiaojiang , Berel Dror , Tighiouart Mourad , Wiedemeyer Wolf Ruprecht , Karlan Beth , Orsulic Sandra 
Published: August 2014

Abstract
Despite the clinical and histopathological similarities in initial disease presentation, patients with advanced ovarian cancer rapidly develop chemoresistance and succumb to the disease. In order to identify genes that are associated with poor patient survival, we analyzed microarray datasets of 795 advanced ovarian cancer patients and correlated gene expression levels with clinical data. We identified a 60-gene signature that was strongly associated with poor survival. Many genes in the signature were stromal genes, including POSTN, FN1, COL11A1, COL6A1, COL3A1, LOX, TIMP3, and VCAN. The same stromal signature was enriched in ovarian cancer metastases and in a cisplatin-resistant A2780 human ovarian cancer cell line. Expression of many stromal genes was induced by TGFβ1 and the effect was reversed by A83-01, a potent TGFβ1 inhibitor. Interestingly, we found that ovarian cancer stem cells (CSC) also express TGFβR2 and several TGFβ1-target genes, including COL6A1 and COL3A1, which were previously implicated in cisplatin resistance. Culturing of A2780 cells on collagen substrate resulted in increased cisplatin resistance and expansion of the CSC population. Our results suggest that TGFβ1 signaling induces stromal gene expression and forms a favorable microenvironment for ovarian CSC, thereby leading to cisplatin resistance and poor patient survival.
Citation Format: Dong-Joo Cheon, Yunguang Tong, Myung-Shin Sim, Xiaojiang Cui, Dror Berel, Mourad Tighiouart, Wolf Ruprecht Wiedemeyer, Beth Karlan, Sandra Orsulic. Stromal gene signature regulated by TGFβ signaling predicts poor clinical outcome in ovarian cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1511. doi:10.1158/1538-7445.AM2013-1511
Abstract 153: Hypothyroidism and hyperthyroidism in relation to endometrial cancer: A prospective study.
Authors: Kueck Angela , Kang Jae Hee , Stevens Richard , Curhan Gary , Alexander Erik , Rosner Bernard , DeVivo Immaculata , Tworoger Shelley 
Published: August 2014

Abstract
Background
Thyroid hormones may be involved in tumorigenesis and metastasis in hormone sensitive cancers. Thyroid hormones strongly influence the menstrual cycle, implantation and fertility, suggesting that thyroid hormones also could play a role in the development of endometrial cancer (EC), which is hormone-sensitive. No prospective studies have examined this association.
Methods
We prospectively evaluated the association between self-reported physician-diagnosed hypothyroidism and hyperthyroidism in the Nurses’ Health Study (NHS) from 1976 - 2010. Reports of thyroid dysfunction were based on self-report on biennial follow-up questionnaires, and have shown high validity when compared to medical records. Incident EC cases were confirmed with medical, pathology and death records. Multivariate rate ratios (RRs) for endometrial cancer were calculated, adjusting for major EC risk factors (i.e., body mass index, smoking, parity, age at last birth, oral contraceptive use, family history, age at menarche, age at menopause, postmenopausal hormone use, type 2 diabetes, and height).
Results
During 34 years of follow-up in NHS, we documented 917 cases of incident EC. Compared to those without any reported thyroid dysfunction, the multivariable RR for hypothyroidism was 0.99 (95% CI, 0.75-1.30) and the null associations were consistent across categories of time since hypothyroidism diagnosis. The multivariable RR for hyperthyroidism was 1.38 (95% CI 0.79 - 2.41). An association was observed with longer time since hyperthyroidism diagnosis (median time since hyperthyroidism diagnosis was 6 years in NHS); the RR for EC associated with 6+ years since hyperthyroidism diagnosis was 2.08 (95% CI, 1.02, 4.23).
Conclusions
Overall self-reported hypothyroidism and hyperthyroidism were not associated with risk of EC; however, longer time since hyperthyroidism diagnosis may be associated with an increased risk of EC. Due to the overall small number of cases with hyperthyroidism, on-going analyses will incorporate results from the Nurses’ Health Study II to increase power for these analyses.
Citation Format: Angela Kueck, Jae Hee Kang, Richard Stevens, Gary Curhan, Erik Alexander, Bernard Rosner, Immaculata DeVivo, Shelley Tworoger. Hypothyroidism and hyperthyroidism in relation to endometrial cancer: A prospective study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 153. doi:10.1158/1538-7445.AM2013-153
Abstract 1542: Th1 and Th2 cytokines determine how CD40 activation changes human macrophage function in vitro.
Authors: Luheshi Nadia , Davies Gareth C. , Poon Edd , McCourt Matthew , Legg James W. 
Published: August 2014

Abstract
Tumour associated macrophages (TAM) often adopt an M2-like immunosuppressive phenotype, promoting tumour growth and metastasis. However, TAM display phenotypic plasticity, and can be repolarised by agents including CD40 agonists to a Th1-immunostimulatory, tumoricidal M1 phenotype, inhibiting tumour growth. T cell-activating therapies synergise with CD40 agonists to induce more extensive TAM repolarisation and tumour growth inhibition, indicating that T cell-derived cytokines may enhance CD40 agonist effects on TAM. We therefore set out to determine how Th1 and Th2 cytokines shape the functional consequences of CD40 activation on human macrophages in vitro. We report that CD40 ligand (CD40L) activates human monocyte-derived macrophages in a similar, but not identical fashion to bacterial LPS in the absence of Th1 or Th2 cytokines. Under these conditions, CD40L activated macrophages adopt an M2-like phenotype, with low tumoricidal activity and producing high levels of immunosuppressive IL-10. The Th1 cytokine IFNγ enhanced anti-tumour functions of CD40-activated macrophages, promoting a switch from immunosuppressive IL-10 to Th1-immunostimulatory IL-12p70 production, and enhancing direct tumoricidal activity. We found that the Th2 cytokines IL-4 and IL-13 also enhanced IL-12p70 production by CD40L-activated macrophages, but, unlike IFNγ, these cytokines did not inhibit IL-10 production. IL-4 and IL-13 also promoted a smaller enhancement in CD40-induced macrophage tumoricidal activity than IFNγ. Thus the presence of Th1 / 2 T cell-derived cytokines in the tumour microenvironment may shape the outcome of CD40 agonist therapy by modulating CD40 agonist effects on TAM.
Citation Format: Nadia Luheshi, Gareth C. Davies, Edd Poon, Matthew McCourt, James W. Legg. Th1 and Th2 cytokines determine how CD40 activation changes human macrophage function in vitro. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1542. doi:10.1158/1538-7445.AM2013-1542
Abstract 1544: Control of tumor-associated macrophage alternative activation by MIF.
Authors: Yaddanapudi Kavitha , Putty Kalyani , Rendon Beatriz , Lamont Gwyneth , Faughn Jonathan , Mitchell Robert 
Published: August 2014

Abstract
Tumor stromal alternatively activated macrophages are important determinants of anti-tumor T lymphocyte responses, intratumoral neovascularization and metastatic dissemination. Our recent efforts to investigate the mechanism of macrophage migration inhibitory factor (MIF) in antagonizing anti-melanoma immune responses reveal that macrophage-derived MIF is necessary for maximal macrophage alternative activation in melanoma-bearing mice. Both peripheral and tumor-associated macrophages (TAMs) isolated from melanoma bearing MIF-deficient mice display elevated pro-inflammatory cytokine expression and reduced anti-inflammatory, immunosuppressive and pro-angiogenic gene products compared to macrophages from tumor bearing MIF wildtype mice. Moreover, TAMs and myeloid-derived suppressor cells (MDSCs) from MIF-deficient mice exhibit reduced T lymphocyte immunosuppressive activities than do those from their wildtype littermates. Corresponding with reduced tumor immunosuppression and neoangiogenic potential by TAMs, MIF-deficiency confers protection against transplantable subcutaneous melanoma outgrowth and melanoma lung metastatic colonization. Finally, we report for the first time that our previously discovered MIF small molecule antagonist, 4-iodo-6-phenylpyrimidine (4-IPP), recapitulates MIF-deficiency in vitro and in vivo and attenuates tumor polarized macrophage alternative activation, immunosuppression, neoangiogenesis and melanoma tumor outgrowth. These studies are the first to describe a functional contribution by MIF to tumor-associated macrophage alternative activation and provide justification for immunotherapeutic targeting of MIF in melanoma patients.
Citation Format: Kavitha Yaddanapudi, Kalyani Putty, Beatriz Rendon, Gwyneth Lamont, Jonathan Faughn, Robert Mitchell. Control of tumor-associated macrophage alternative activation by MIF. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1544. doi:10.1158/1538-7445.AM2013-1544
Abstract 1547: Tumor-derived macrophage Migration Inhibitory Factor and interleukin-6 cooperated in hypoxic accumulation of CD11b+Gr-1+ myeloid cells.
Authors: Zhu Guiquan , Tang Yaling , Li Ling , Liang Xinhua 
Published: August 2014

Abstract
Recently, myeloid derived suppressor cells (MDSCs) have gained much attention due to their role in tumor immunity suppression as well as promotion of angiogenesis, tumor cell invasion, and metastases. However, the mechanisms that regulate MDSCs recruitment have not been well clarified. Here, we demonstrated that hypoxic tumor microenvironment stimulate the recruitment of MDSCs through increased production of macrophage migration inhibitory factor (MIF) and interleukin-6 (IL-6) by head and neck squamous cell carcinoma (HNSCC) cells. Knock-down (KD) of HIF-1/2α in HNSCC cells decreased MIF level but did not inhibit the MDSCs migration, because HIF-1/2α KD increased NF-κB activity which further enhanced IL-6 secretion. In vivo administration of neutralizing IL-6 antibody and inhibitors against MIF and NF-κB decreased MDSCs accumulation, accompanied by reduced micro-vessel density (MVD), lymphatic vessel density (LVD), and xenograft tumor growth. The supplementation of MDSCs increased MVD, LVD, and xenograft tumor growth. In conclusion, hypoxic HNSCC cells may stimulate the accumulation of MDSCs through secreting MIF and IL-6. This process is mediated by interactions between NF-κB and HIF-1/2α. Strategies targeting hypoxic tumor microenvironment may represent attractive approaches to HNSCC therapy.
[G Zhu and Y Tang contributed equally to this paper.]
Citation Format: Guiquan Zhu, Yaling Tang, Ling Li, Xinhua Liang. Tumor-derived macrophage Migration Inhibitory Factor and interleukin-6 cooperated in hypoxic accumulation of CD11b+Gr-1+ myeloid cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1547. doi:10.1158/1538-7445.AM2013-1547
Abstract 1552: Cigarette smoke induces TNF-α secretion from macrophages through a pathway consisting of PPARγ, MUC1, ERK and JNK.
Authors: Xu Xiuling , Padilla Mabel T. , Wells Alexandria , Kim Kwang Chul , Lin yong 
Published: August 2014

Abstract
The glycoprotein Mucin 1 (MUC1 in human and Muc1 in animals) is expressed in the lung and has been shown to be associated with lung carcinogenesis. Recently we have found that cigarette smoke (CS) significantly increased MUC1 expression in mouse lung macrophages and that MUC1 is required for CS-induced tumor necrosis factor-alpha (TNF-α) secretion from macrophages. Because CS potently elicits chronic pulmonary inflammation that is important for the development of lung cancer, we investigated the cell signaling pathways for CS-induced MUC1 expression and MUC1-mediated TNF-α secretion in macrophages using an in vitro model. The results showed that: CS extract (CSE) strongly induced MUC1 expression at both the mRNA and protein levels; Suppression of PPARγ effectively blocked CSE-induced MUC1 expression in THP1 cells, suggesting CSE induces MUC1 expression through PPARγ-mediated transcription; The induction of TNF-α expression was effectively blocked when ERK and JNK were blocked, suggesting these pathways are involved in CSE-induced TNF-α expression in macrophages; Knockdown of MUC1 significantly suppressed CSE-induced ERK and JNK activation; and Suppression of PPARγ that effectively blocked CSE-induced MUC1 expression also inhibited CSE-induced TNF-α secretion from macrophages. Thus, our results suggest a possible involvement of a signaling pathway consisting of PPARγ, MUC1 and ERK/JNK for CSE-induced TNF-α secretion from macrophages that may contribute to inflammation-associated lung cancer development. Note: This work is supported by the NIH/NIEHS grant 1R01ES017328.
Citation Format: Xiuling Xu, Mabel T. Padilla, Alexandria Wells, Kwang Chul Kim, yong Lin. Cigarette smoke induces TNF-α secretion from macrophages through a pathway consisting of PPARγ, MUC1, ERK and JNK. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1552. doi:10.1158/1538-7445.AM2013-1552