bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1090: Development of predictive biomarkers for anti-TGF-beta therapy
Authors: Yang Yu-an , Weng Jia , Welsh Michael , Ford Heide L. , Lonning Scott M. , Wakefield Lalage 
Published: June 2012

Abstract
TGF-betas are pleiotropic growth factors with complex roles in tumorigenesis. The TGF-betas have many activities that could promote metastasis, including the enhancement of invasion and migration, the promotion of angiogenesis, and the suppression of immune surveillance. Overexpression of TGF-beta in many advanced human tumors correlates with metastasis and poor prognosis, and there is now considerable interest in developing TGF-beta antagonists for cancer therapy. Indeed, a Phase I oncology trial using a fully humanized anti-TGF-beta monoclonal antibody was recently successfully completed. There is now an urgent need for good predictive biomarkers for patient stratification in future clinical trials. Using different syngeneic mouse transplant models of metastatic breast cancer, we have found that anti-TGF-beta antibodies suppress metastasis in several models, including the widely-used 4T1 model. However, TGF-beta antibody treatment has no effect or even stimulates metastasis in other models. This panel of mouse models with differing responses to anti-TGF-beta therapy represents a powerful experimental platform for the identification of predictive biomarkers. Based on existing knowledge, we have assessed a number of plausible candidates. Global gene expression analyses have defined several distinct molecular subtypes of breast cancer with different clinical characteristics. The “Claudin-low” subtype is a particularly poor prognosis subset of the triple negative ER-PR-HER2- breast cancers. By definition these tumors have low claudin and E-cadherin expression and a mesenchymal phenotype. Since TGF-betas are strong inducers of the mesenchymal phenotype, the claudin-low subtype may represent a particularly good target for anti-TGF-beta therapy. Similarly, overexpression of the homeobox protein Six-1 has recently been shown to cause TGF-beta to switch from tumor suppressor to pro-metastatic factor in breast cancer and might also be a predictor of a positive therapeutic response to TGF-beta antagonism. Here we have assessed the claudin-low status of a number of mouse mammary tumor models, by RTQ-PCR for key markers, using cells cultured in vitro. In addition, we determined nuclear Six1 levels by Western blot. Neither claudin-low status nor Six1 expression were predictive of response to anti-TGF-beta therapy. We are assessing additional candidate biomarkers and moving forward with discovery approaches.
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 1090. doi:10.1158/1538-7445.AM2011-1090
Abstract 1098: Interactions between P53 and IGF2 in human esophageal adenocarcinoma tissues and cell lines
Authors: Zhao Ronghua , Casson Alan G. 
Published: June 2012

Abstract
To define the role of the insulin-like growth factor (IGF) axis in esophageal adenocarcinoma (EADC), the objective of this study was to evaluate interactions between IGF2 and P53 in a well characterized series of surgically-resected esophageal tissues and the following cell lines: Het1A (derived from immortalized normal esophageal epithelium), OE33 and JH-EsoAd1 (each derived from a primary EADC). Nucleic acids were extracted from 68 primary EADC (and matched histologically normal) tissues. PCR was performed on gDNA and RT-PCR on RNA followed by ApaI digestion to identify informative (heterozygous) cases and imprinting status, respectively. Expression of IGF2 mRNA was determined by quantitative PCR, and of IGF2 and P53 protein by Western analysis and immunohistochemistry. Molecular findings in tissues were correlated with pathologic and clinical characteristics including patient survival. Functional studies utilizing cell lines evaluated IGF2/P53 interactions. Of 44 informative cases, P53 protein overexpression was significantly higher in normally imprinted tumors (12/30) vs. tumors with loss of IGF2 imprinting (1/14; p&lt;0.05). Multivariable logistic regression confirmed IGF2 imprinting status to be independently associated with P53 expression (OR 0.12, 95% CI 0.01-1.00; p=0.05). Tumors overexpressing both IGF2 and P53 were found to be of advanced stage with poor survival. In patients below age 65 years, IGF2 mRNA expression was significantly higher in tumors with wild type P53, and multivariate analysis showed IGF2 mRNA expression to be independently associated with p53 mutation (OR 0.74, 95% CI 0.58-0.94; p&lt;0.05) and P53 protein expression (OR 0.83, 95% CI 0.69-1.00; p&lt;0.05). Whereas treatment of Het1A cells with IGF2 significantly increased P53 expression (1.34+/-0.06 vs. 1.00+/-0.00 untreated cells; p=0.003), IGF2 did not modulate P53 expression in either of the two tumor cell lines (OE33 and JH-EsoAd1). IGF1 Receptor (IGF1R) inhibition with AG1024 reduced P53 expression only in OE33 (0.48+/-0.22 vs. 1.00+/-0.00 untreated cells; p=0.05) and JH-EsoAd1 (0.71 +/- 0.23 vs. 1.00+/- 0.00 untreated; p = 0.15) cells, an effect not reversed by IGF2 treatment. In conclusion: 1) these studies identify novel molecular regulatory interactions between P53 and IGF2 in esophageal malignancy, which are dependent on IGF2 imprinting status and tissue/cell type. 2) Overexpression of both IGF2 and P53 in esophageal tumors is associated with aggressive disease in younger patients (below age 65 years), and may represent clinically useful biomarkers to define a biologically distinct subset of EADC.
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 1098. doi:10.1158/1538-7445.AM2011-1098
Abstract 1109: Characterization of hepatoma-derived growth factor (HDGF) as a novel survival related protein in prostate cancer cells
Authors: Munirathinam Gnanasekar , Shetty Aditya , Samykutty Abhilash , Dakshinamoorthy Gajalakshmi , Zheng Guoxing , Chen Aoshuang , Bosland Maarten C. , Kajdacsy-Balla André , Kalyanasundaram Ramaswamy 
Published: June 2012

Abstract
Prostate cancer (PCa) is a leading cause of death by cancer in men, resulting in approximately 32,000 deaths each year. While the cause of PCa is not clearly known at this time, some risk factors include age, diet, race, and activation of certain oncogenes. Hepatoma-derived growth factor (HDGF) is a recently discovered oncogene and a key mitogenic growth factor which is activated in lung, liver, and skin cancers, however, its role in the development of PCa is unknown. Therefore, the goal of this study is to characterize the role of HDGF in prostate carcinogenesis. A normal prostate cell line, RWPE-1, and four different PCa cell lines, LNCaP, 22RV1, DU145, and PC-3, were analyzed for their expression level of HDGF by western blot analysis. Results of this evaluation revealed that HDGF is over-expressed in multiple PCa cell lines while minimally expressed in RWPE-1 cells. When the HDGF gene is ectopically over-expressed in normal RWPE-1 cells, proliferative rate was increased by 1.5 fold compared to the normal cells, suggesting that HDGF has growth stimulating activity. On the contrary, down regulation of HDGF expression by siRNA significantly inhibited the survival of both androgen dependent (LNCaP) and androgen independent (PC-3) PCa cells. DNA content analysis of RWPE-1 cells stably expressing HDGF by flow cytometry showed that the majority of the cells were in the G2/M phase (55%) of the cell cycle while only 28% of the control RWPE-1 cells were at G2/M phase implying HDGF may have a mitotic function in prostate cells. Furthermore, AKT (phosphorylated form) and NFκB (p65 domain) signaling molecules were found to be activated in RWPE-1 cells expressing HDGF. This activation resulted in the increase of anti-apoptotic molecules Cyclin-E and BCL-2 and the simultaneous decrease in the pro-apoptotic molecule Bax. Activation of AKT-NFκB pathway plays a vital role in the carcinogenesis of several cancers, including PCa. Thus, HDGF over-expression may play a role in regulating this survival pathway in prostate carcinogenesis. Collectively, the results of this study suggest that HDGF is a key player in the development of PCa and may serve as a target for chemopreventive or chemotherapeutic strategies in PCa.
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 1109. doi:10.1158/1538-7445.AM2011-1109
Abstract 1117: Macrophage migration inhibitory factor (MIF) plays a critical role in clear cell renal carcinoma
Authors: Wright Bradley M. , Du Weinan , Li Xiaofeng , Finke James , Rini Brian I. , Zhou Ming , He Huiying , Lal Priti , Welford Scott M. 
Published: June 2012

Abstract
Clear cell renal carcinoma (CCRC) is the most common form of renal cancer, resulting in 50,000 new cases per year in the US, and greater than 10,000 deaths. CCRC is frequently characterized by alterations in the von Hippel-Lindau protein (VHL), an E3 ligase that mediates oxygen dependent degradation of the alpha subunit of the hypoxia inducible factor (HIF). Activation of HIF and many of its transcriptional target genes are critical for renal tumorigenesis. The macrophage migration inhibitor factor (MIF) is a pleiotropic cytokine that has roles in inflammation, cell signaling, and cell cycle regulation. MIF is regulated by HIF, and is expressed in a variety of tumor types wherein MIF expression correlates with poor outcome. Functionally, MIF can negatively regulate p53, and thus may be particularly relevant in cancers like clear cell carcinoma in which p53 is not commonly mutated. The purpose if this study is to determine the role of MIF in CCRC.
In order to determine if MIF is expressed in CCRC patient samples, we stained tumor microarrays with over 95 primary CCRC tumors for MIF expression. In keeping with its reported regulation by the VHL/HIF pathway, MIF demonstrated high expression in greater than 90% of the tumors compared to normal kidney samples. Likewise, in CCRC tumor cell lines MIF expression was highly expressed compared to cell lines in which VHL expression has been reconstituted. To determine the significance of MIF expression in CCRC tumor cell lines, MIF was depleted using two independent shRNAs and we observed significant decreases cell proliferation and clonogenic survival in a variety of CCRC cell lines. These observations were replicated by silencing the expression of the MIF receptor CD74, suggesting the MIF signaling pathway is intact and functional CCRC.
At the mechanistic level, MIF is known to inhibit the function of p53 through promotion of MDM2 mediated degradation. To assess whether the role of MIF in CCRC is to regulate p53, we determined the effects on p53 signaling when MIF expression was inhibited. We found that inhibition of MIF lead to an increase in p53 stability and subsequent expression of the canonical p53 target gene p21. Together these observations suggest that MIF expression may play a critical role as a target of the HIF/VHL pathway that leads to the development of clear cell carcinoma.
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 1117. doi:10.1158/1538-7445.AM2011-1117
Abstract 1119: Interplay between EGFRvIII and c-Met in glioblastoma multiforme
Authors: Saunders Vanessa , Ling Yuan Yuan , Anderson Jessica , Duckett Derek 
Published: June 2012

Abstract
Glioblastoma multiforme (GBM) is a highly invasive and lethal brain tumor which is associated with a high recurrence rate after surgery and an increased resistance to irradiation and chemotherapies. Consequently, patients suffering from GBM have a poor prognosis and a high mortality rate with an average life expectancy of less than 15 months. Key signaling components, especially receptor tyrosine kinases (RTKs), are aberrantly activated in GBM. The most frequent is the epidermal growth factor receptor (EGFR) and here the most commonly activated form, EGFRvIII, augments GBM invasiveness, promotes therapy resistance and connotes poor prognosis. There are five EGFR approved inhibitors and interestingly clinical studies have indicated that targeting the activity of the EGFR in association with conventional GBM therapies does little to inhibit tumor growth. The underlying mechanistic reasoning for this poor response are not understood and may reflect EGFR-induced trans-activation of other RTKs such as the hepatocyte growth factor receptor (c-Met), or uncoupling of EGFR signaling from its downstream mediators. Several studies have indicated that EGFR can trans-activate c-Met and consequently the dual targeting of both EGFR and c-Met significantly decreases the growth of EGFRvIII expressing tumor xenografts, indicating that inhibiting both EGFR and c-Met activity may prove beneficial in GBM therapy. Currently, the only known ligand for c-Met is the hepatocyte growth factor (HGF). Thus we hypothesize that EGFR induced HGF production is critical for the increased tumorgenicity observed in EGFRvIII expressing GBM cells. Using GBM cell lines we show that c-Met activation is increased in GBM cells that both stably and transiently express EGFRvIII. Furthermore, conditioned media taken from GBM cells expressing EGFRvIII can activate c-Met signaling in GBM cells that lack EGFRvIII. In both instances we see that the kinase activity of the EGFRvIII partially contributes to the production of HGF and the activation of c-Met in GBM cells. Aberrant c-Jun terminal kinase signaling (JNK) can be detected in the majority of patient GBMs. Using GBM cells stably lacking JNK2α2 we identify JNK2α2 signaling as a potential mechanism behind EGFRvIII activation of c-Met via the production of HGF in EGFRvIII GBM expressing cells. Taken together our data describes a novel role for JNK2α2 in mediating GBM tumorgenicity through the regulation of HGF production and the subsequent activation of c-Met signaling in GBM.
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 1119. doi:10.1158/1538-7445.AM2011-1119
Abstract 1122: Insulin receptor expression and survival of patients with non-small cell lung cancer
Authors: Kim Jin-Soo , Kim Edward S. , Liu Diane , Lee J. Jack , Solis Luisa , Behrens Carmen , Lippman Scott , Hong Waun Ki , Wistuba Ignacio I. , Lee Ho-Young 
Published: June 2012

Abstract
Purpose: The purpose of this study was to characterize insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) expression in patients with non-small cell lung cancer (NSCLC).
Methods: A total of 459 patients who underwent curative resection of NSCLC were studied (median follow-up duration, 4.01 years). Expression of the IR and IGF-1R protein in tumor specimens was assessed immunohistochemically using tissue microarrays.
Results: The cytoplasmic IR score was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC) whereas cytoplasmic IGF-1R was higher in patients with SCC than those with ADC. Neither IR nor IGF-1R expression was associated with sex, smoking history, or clinical stage. Patients with positive IR or IGF-1R expression levels had poor recurrence-free (3.8 vs. 3.3 years; 3.8 vs. 2.0 years, respectively) but similar overall survival durations. Patients with high expression levels both IR and IGF-1R had shorter recurrence-free and overall survival compared to those with low levels of IR and/or IGF-1R expression. IGF-1R and IR expressions were negatively correlated with survival duration of patients with ADC and SCC, respectively. Finally, a multivariate analysis revealed the impact of IR, but not IGF-1R, as an independent prognostic predictor of survival: hazard ratio (HR) for OS, 1.005 (95% confidence interval [CI], 1.001 – 1.010], HR for RFS, 0.608 (95% CI, 1.001 – 1.009) when tested as a continuous variable.
Conclusions: Overexpression of IR, but not IGF-1R, appears to foretell a poor survival among patients with NSCLC, especially those with SCC. Thus, expression of IR has a negative prognostic value and future clinical trials with therapy interventions of IR regulation should be under the consideration for this patient population.
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 1122. doi:10.1158/1538-7445.AM2011-1122
Abstract 1125: The insulin-like growth factor (IGF) axis is involved in normal prostate differentiation and downregulated in local prostate cancer
Authors: Massoner Petra , Rennau Michael Ladurner , Heidegger Isabel M. , Kloss-Brandstätter Anita , Schäfer Georg , Seifarth Christof , Klocker Helmut 
Published: June 2012

Abstract
Introduction and Objectives: Clinical trials targeting the insulin-like growth factor 1 receptor (IGF1R) in different tumors, including breast cancer, colorectal cancer, leukemia (ALL, CML), non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer and sarcomas are underway. Encouraging data from phase II studies in NSCLC and sarcomas led to rapid development of phase-III studies. However, a phase-III study with an anti-IGF1R antibody combined with erlotinib in advanced NSCLC was terminated recently for safety reasons and lack of efficiency (ClinicalTrials.gov Identifier: NCT00673049). Have we possibly moved to early to clinical trials without entirely understanding the role of the IGF axis in normal and cancer development?
The IGF1R is part of a tightly regulated molecular network named IGF axis. The IGF axis is implicated in tumor development and progression, but also exerts essential functions in normal tissues, including control of growth processes, tissue homeostasis, differentiation and metabolism.
Methods: Here we analyzed the mRNA expression level of the all members of the IGF axis, including IGF1, IGF2, IGFBP1-IGFBP6, IGF1R, IGF2R and INSR in microdissected tissue specimens of local prostate cancer. We compared IGF expression levels in malignant and benign prostate areas in both, the epithelial and the stromal compartment. Furthermore we investigated whether IGF expression levels are changed during normal prostate differentiation and describe a novel cellular model for prostate differentiation.
Results: We show that the IGF axis is not up- but downregulated in local prostate cancer, in both the epithelial and the stromal compartment. Using cellular models we demonstrate that the IGF axis is induced during normal prostate epithelial differentiation and confirm herewith that the IGF axis is required for tissue homeostasis and normal epithelial differentiation in the prostate.
Conclusions: Our data confirm a pivotal role of the IGF axis during normal prostate differentiation, which may overcomes its pro-oncogenic effect in local prostate cancer. Treatments of local prostate cancer with IGF1R inhibitors cannot be advised based on these data.
Source of Funding: COMET center Oncotyrol and Tyrolean Cancer Foundation.
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 1125. doi:10.1158/1538-7445.AM2011-1125
Abstract 113: Aberrant DNA methylation of the HIF-1α inhibitor gene CITED4 in breast cancer
Authors: Huang Katie T. , Takano Elena A. , Mikeska Thomas , Byrne David J. , Dobrovic Alexander , Fox Stephen B. 
Published: June 2012

Abstract
CBP/p300-interacting transactivator with ED-rich carboxy-terminal domain, 4 (CITED4) inhibits the interaction between HIF-1α and p300/CBP thereby reducing expression of downstream hypoxia responsive genes. Since we have previously shown that diminished levels of nuclear CITED4 as a consequence of down-regulation or translocation to the cytoplasm are correlated with HIF-1α elevation in breast cancer, we hypothesized that either hypermethylation or somatic mutation of the CITED4 gene may also underlie elevated HIF-1α levels in breast tumors.
CITED4 DNA methylation and mutation were analyzed in 168 breast carcinoma samples and 23 cancer cell lines using methylation-sensitive high resolution melting (MS-HRM) and DNA sequencing, respectively. Although no somatic CITED4 mutation was found, there was evidence of CITED4 promoter region methylation in five breast carcinoma samples, and three breast cancer cell lines (heterogeneously methylated in Hs578T and MDA-MB-231, and fully methylated in MDA-MB-453). There was a significant association between low CITED4 mRNA and high methylation in Hs578T (P = 0.0001) and MDA-MB-231 (P &lt; 0.0001) and no expression was found in fully methylated cell line MDA-MB-453.
Methylated CITED4 breast cancer cell lines were treated with 5-aza-2-deoxycytidine (DAC) and/or trichostatin A to evaluate the regulation of CITED4 expression through DNA methylation. CITED4 expression was re-expressed in fully methylated MDA-MB-453 cell line and increased expression in MDA-MB-231 (21.9-fold) and Hs578T (4.9-fold) after DAC mediated demethylation, and treatment with trichostatin A alone also resulted in increased CITED4 expression. A synergistic effect was seen after the combined treatment of DAC and trichostatin A.
Furthermore, re-expressed CITED4 expression after DAC treatment may reduce HIF-1α and its downstream genes activity. MDA-MB-231 breast cancer cell line treated with DAC under hypoxia (0.1% oxygen) and demonstrated the downregulation of HIF-1α downstream genes VEGFA and SLC2A1 (P = 0.0029) when compared with the untreated MDA-MB-231 cell line under hypoxia. Immunohistochemstry also demonstrated that HIF-1α and downstream CA9 levels had decreased after CITED4 re-expressed under the hypoxic condition from 23% of positive staining in control to 10% after DAC treatment for HIF-1α and from 5 % to 3% for CA9.
These data suggest that, CITED4 gene expression can be epigenetically silenced through DNA methylation in breast cancer, which may enhance the activity of HIF in developing aggressive breast cancer phenotypes.
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 113. doi:10.1158/1538-7445.AM2011-113