bluuebunny/crossref_metadata_2025_split huggingface dataset:
Killer Dendritic Cells Link Innate and Adaptive Immunity against Established Osteosarcoma in Rats
Authors: Chauvin Camille , Philippeau Jean-Marie , Hémont Caroline , Hubert Francois-Xavier , Wittrant Yohann , Lamoureux Francois , Trinité Benjamin , Heymann Dominique , Rédini Françoise , Josien Régis 
Published: November 2008

Abstract
We have previously reported that a distinct subset of splenic CD4− rat dendritic cells (DC) induces a rapid and caspase-independent apoptosis-like cell death in a large number of tumor cells in vitro. The killing activity of these killer DC (KDC) was restricted to their immature state and was immediately followed by their engulfment of the apoptotic target cells, suggesting that these KDC could directly link innate and adaptive immunity to tumors. Here, we addressed this question using a transplantable model of rat osteosarcoma. First, we showed that rat KDC have an MHC II+CD103+CD11b+NKp46− phenotype and are therefore distinct from natural killer cells, which are MHC II−CD103−CD11b−NKp46+. KDC numbers could be specifically and strongly (up to 10-fold) enhanced by Flt3L in vivo. The OSRGa cell line derived from the osteosarcoma tumor was killed and phagocytosed in vitro by both normal and Flt3L-induced splenic KDC. Such tumor antigen–loaded KDC were used to s.c. vaccinate progressive tumor-bearing rats. Vaccination with OSRGa-loaded KDC but not KDC loaded with irrelevant tumor cells (Jurkat) delayed tumor progression or even induced tumor regression. This vaccine effect was not observed in CD8 T cell–depleted animals and protective against tumor rechallenge. These results suggest that KDC possess the intrinsic capability not only to kill and then engulf tumor cells but also to efficiently cross-present tumor cell–derived antigen in vivo and subsequently induce an adaptive antitumor immune response. [Cancer Res 2008;68(22):9433–40]
Interplay between the Nuclear Receptor Pregnane X Receptor and the Uptake Transporter Organic Anion Transporter Polypeptide 1A2 Selectively Enhances Estrogen Effects in Breast Cancer
Authors: Meyer zu Schwabedissen Henriette E. , Tirona Rommel G. , Yip Cindy S. , Ho Richard H. , Kim Richard B. 
Published: November 2008

AbstractThe ligand-activated nuclear receptor pregnane X receptor (PXR) is known to play a role in the regulated expression of drug metabolizing enzymes and transporters. Recent studies suggest a potential clinically relevant role of PXR in breast cancer. However, the relevant pathway or target genes of PXR in breast cancer biology and progression have not yet been fully clarified. In this study, we show that mRNA expression of organic anion transporter polypeptide 1A2 (OATP1A2), a transporter capable of mediating the cellular uptake of estrogen metabolites, is nearly 10-fold greater in breast cancer compared with adjacent healthy breast tissues. Immunohistochemistry revealed exclusive expression of OATP1A2 in breast cancer tissue. Interestingly, treatment of breast cancer cells in vitro with the PXR agonist rifampin induced OATP1A2 expression in a time-dependent and concentration-dependent manner. Consistent with its role as a hormone uptake transporter, induction of OATP1A2 was associated with increased uptake of estrone 3-sulfate. The rifampin response was abrogated after small interfering RNA targeting of PXR. We then identified a PXR response element in the human OATP1A2 promoter, located ∼5.7 kb upstream of the transcription initiation site. The specificity of PXR-OATP1A2 promoter interaction was confirmed using chromatin immunoprecipitation. Importantly, we used a novel potent and specific antagonist of PXR (A-792611) to show the reversal of the rifampin effect on the cellular uptake of E1S. These data provide important new insights into the interplay between a xenobiotic nuclear receptor PXR and OATP1A2 that could contribute to the pathogenesis of breast cancer and may also prove to be heretofore unrecognized targets for breast cancer treatment. [Cancer Res 2008;68(22):9338–47]
Effect of Fenretinide and Low-Dose Tamoxifen on Insulin Sensitivity in Premenopausal Women at High Risk for Breast Cancer
Authors: Johansson Harriet , Gandini Sara , Guerrieri-Gonzaga Aliana , Iodice Simona , Ruscica Massimiliano , Bonanni Bernardo , Gulisano Marcella , Magni Paolo , Formelli Franca , Decensi Andrea 
Published: November 2008

Abstract
The prevalence of metabolic syndrome is increasing along with breast cancer incidence worldwide. Because fenretinide improves insulin action and glucose tolerance in insulin-resistant obese mice and because tamoxifen has shown to regulate several markers involved in metabolic syndrome, we sought to investigate the effect of fenretinide or tamoxifen at low dose on features linked to insulin resistance in premenopausal women at risk for breast cancer. We randomized 235 women to low-dose tamoxifen (5 mg/daily), fenretinide (200 mg/daily), or their combination or placebo for 2 years. We used the homeostasis model assessment (HOMA; fasting insulin × glucose/22.5) to estimate insulin sensitivity. Women were considered to improve insulin sensitivity when they shifted from a HOMA ≥2.8 to &lt;2.8. There was no effect of fenretinide or tamoxifen on HOMA overall, but overweight women (body mass index, ≥25 kg/m2) had a 7-fold greater probability to normalize HOMA after 2 years of fenretinide treatment [odds ratio (OR), 7.0; 95% confidence interval (95% CI), 1.2–40.5], with 25% of women improving their insulin sensitivity, whereas tamoxifen decreased insulin sensitivity by almost 7 times compared with subjects not taking tamoxifen (OR, 0.15; 95% CI, 0.03–0.88). In this group only, 5% improved their insulin sensitivity. Interestingly, women with intraepithelial or microinvasive neoplasia had higher HOMA (3.0) than unaffected subjects (2.8; P = 0.07). Fenretinide can positively balance the metabolic profile in overweight premenopausal women and this may favorably affect breast cancer risk. Furthermore, features of the metabolic syndrome should be taken into consideration before proposing tamoxifen for breast cancer prevention. The clinical implications of these results require further investigations. [Cancer Res 2008;68(22):9512–8]
Does the Renin-Angiotensin System Participate in Regulation of Human Vasculogenesis and Angiogenesis?
Authors: Khakoo Aarif Y. , Sidman Richard L. , Pasqualini Renata , Arap Wadih 
Published: November 2008

Abstract
Several lines of evidence suggest that hypertension and angiogenesis may be related phenomena but a functional link remains elusive. Here, we propose that the renin-angiotensin system (RAS), in addition to its central role in arterial hypertension, also regulates blood vessel formation during normal development and cancer. This mechanistic hypothesis is based on reports of biochemical, genetic, clinical, and epidemiologic data reviewed herein. Species differences between the RAS of rodents and humans likely account for why such a fundamental role in angiogenesis went unrecognized for so long. If proven correct, this hypothesis carries many implications for the medical practices of cardiology, oncology, and neonatology. [Cancer Res 2008;68(22):9112–5]
The Mitogen-Activated Protein Kinase Phosphatase Vaccinia H1–Related Protein Inhibits Apoptosis in Prostate Cancer Cells and Is Overexpressed in Prostate Cancer
Authors: Arnoldussen Yke Jildouw , Lorenzo Petra I. , Pretorius Maria E. , Wæhre Håkon , Risberg Bjørn , Mælandsmo Gunhild M. , Danielsen Håvard E. , Saatcioglu Fahri 
Published: November 2008

Abstract
Androgen ablation during the initial stages of prostate cancer causes regression of the tumor due to an increase in apoptosis and reduced cellular proliferation. However, prostate cancer invariably progresses to an androgen-independent state for poorly understood reasons. Previous studies showed that c-Jun NH2 terminal kinase (JNK) is required for 12-O-tetradecanoylphorbol-13-acetate (TPA)– and thapsigargin (TG)–induced apoptosis in the androgen-responsive prostate cancer cell line LNCaP. Androgens protect LNCaP cells from TPA-induced or TG-induced apoptosis via down-regulation of JNK activation. However, the molecular mechanisms of this inhibition are not clear. Here, we systematically investigated the possible regulation of mitogen-activated protein kinase phosphatases/dual-specificity phosphatases during apoptosis of LNCaP cells and found that Vaccinia H1–related protein (VHR/DUSP3) is up-regulated by androgens during inhibition of apoptosis in LNCaP cells, but not in androgen-independent DU145 cells. Ectopic expression of wild-type VHR, but not a catalytically inactive mutant, interfered with TPA- and TG-induced apoptosis. Consistently, small interfering RNA–mediated knockdown of endogenous VHR increased apoptosis in response to TPA or TG in the presence of androgens. Furthermore, COS7 cells stably expressing wild-type VHR, but not a mutant, had a decrease in JNK phosphorylation. In vivo, VHR expression decreased in the androgen-dependent human prostate cancer xenograft CWR22 upon androgen withdrawal and was inversely correlated to JNK phosphorylation. Expression analysis in human prostate cancer specimens showed that VHR is increased in prostate cancer compared with normal prostate. These data show that VHR has a direct role in the inhibition of JNK-dependent apoptosis in LNCaP cells and may therefore have a role in prostate cancer progression. [Cancer Res 2008;68(22):9255–64]
Angiotensin II Induces DNA Damage in the Kidney
Authors: Schmid Ursula , Stopper Helga , Schweda Frank , Queisser Nina , Schupp Nicole 
Published: November 2008

Abstract
Increased activity of the renin angiotensin system with enhanced levels of angiotensin II leads to oxidative stress with endothelial dysfunction, hypertension, and atherosclerosis. Epidemiologic studies revealed a higher cancer mortality and an increased kidney cancer incidence in hypertensive patients. Because elevated angiotensin II levels might contribute to carcinogenesis, we tested whether angiotensin II induces DNA damage in the kidney. In isolated perfused mouse kidneys, as little as 1 nmol/L angiotensin II caused a significant increase in DNA strand breaks, measured with the comet assay. This damage was independent of the hemodynamic effect of angiotensin II and mediated by the angiotensin II type 1 receptor. Angiotensin II also caused double-strand breaks in the cells of the isolated perfused kidney, detected with an antibody against the double-strand break marker γ-H2AX. Studies in cell culture allowed further characterization of the DNA damage induced by angiotensin II. Single- and double-strand breaks, abasic sites, and 7,8-dihydro-8-oxo-guanine, all types of oxidative DNA lesions, were detected in angiotensin II–treated renal cells. The majority of detected strand breaks was repaired within 1 hour, but double-strand breaks increased and persisted for at least 24 hours. [Cancer Res 2008;68(22):9239–46]
Evidence for an Important Role of CIDEA in Human Cancer Cachexia
Authors: Laurencikiene Jurga , Stenson Britta M. , Arvidsson Nordström Elisabet , Agustsson Thorhallur , Langin Dominique , Isaksson Bengt , Permert Johan , Rydén Mikael , Arner Peter 
Published: November 2008

Abstract
Loss of fat mass in cancer cachexia is linked to increased adipocyte lipolysis; however, the fate of the excess fatty acids (FA) generated by lipolysis is not known. We investigated if the adipocyte-specific gene cell death–inducing DNA fragmentation factor-α–like effector A (CIDEA) could be involved. CIDEA mRNA expression was assessed in s.c. white adipose tissue from 23 cancer cachexia patients, 17 weight-stable cancer patients, and 8 noncancer patients. CIDEA was also overexpressed in adipocytes in vitro. CIDEA expression was increased in cancer cachexia (P &lt; 0.05) and correlated with elevated levels of FAs and reported weight loss (P &lt; 0.001). CIDEA overexpression in vitro increased FA oxidation 2- to 4-fold (P &lt; 0.01), decreased glucose oxidation by 40% (P &lt; 0.01), increased the expression of pyruvate dehydrogenase kinase (PDK) 1 and PDK4 (P &lt; 0.01), and enhanced the phosphorylation (inactivation) of the pyruvate dehydrogenase complex (PDC). Inactivation of PDC facilitates FA oxidation by favoring the metabolism of FAs over glucose to acetyl-CoA. In accordance with the in vitro data, PDK1 and PDK4 expression correlated strongly with CIDEA expression in white adipose tissue (P &lt; 0.001). We conclude that CIDEA is involved in adipose tissue loss in cancer cachexia and this may, at least in part, be due to its ability to inactivate PDC, thereby switching substrate oxidation in human fat cells from glucose to FAs. [Cancer Res 2008;68(22):9247–54]
IκBα Kinase Inhibitor IKI-1 Conferred Tumor Necrosis Factor α Sensitivity to Pancreatic Cancer Cells and a Xenograft Tumor Model
Authors: Zhang Yixian , Gavriil Maria , Lucas Judy , Mandiyan Sreekala , Follettie Max , Diesl Veronica , Sum Fuk-Wah , Powell Dennis , Haney Steve , Abraham Robert , Arndt Kim 
Published: November 2008

Abstract
Tumor necrosis factor α (TNFα) has been used to treat patients with certain tumor types. However, its antitumor activity has been undermined by the activation of IκBα kinase (IKK), which in turn activates nuclear factor-κB (NF-κB) to help cancer cells survive. Therefore, inhibition of TNFα-induced IKK activity with specific IKK inhibitor represents an attractive strategy to treat cancer patients. This study reveals IKI-1 as a potent small molecule inhibitor of IKKα and IKKβ, which effectively blocked TNFα-mediated IKK activation and subsequent NF-κB activity. Using gene profiling analysis, we show that IKI-1 blocked most of the TNFα-mediated mRNA expression, including many genes that play important roles in cell survival. We further show that in vitro and in vivo combination of TNFα with IKI-1 had superior potency than either agent alone. This increased potency was due primarily to the increased apoptosis in the presence of both TNFα and IKI-1. Additionally, IKKβ small interfering RNA transfected cells were more sensitive to the treatment of TNFα. The study suggests that the limited efficacy of TNFα in cancer treatment was due in part to the activation of NF-κB, allowing tumor cells to escape apoptosis. Therefore, the combination of IKI-1 with TNFα may improve the efficacy of TNFα for certain tumor types. [Cancer Res 2008;68(22):9519–24]
Association of Autophagy Defect with a Malignant Phenotype and Poor Prognosis of Hepatocellular Carcinoma
Authors: Ding Zhen-Bin , Shi Ying-Hong , Zhou Jian , Qiu Shuang-Jian , Xu Yang , Dai Zhi , Shi Guo-Ming , Wang Xiao-Ying , Ke Ai-Wu , Wu Bin , Fan Jia 
Published: November 2008

Abstract
Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The role of autophagy and the prognostic value of autophagic genes are largely unknown in HCC. Here, we showed decreased expression of autophagic genes and their corresponding autophagic activity and increased expression of the antiapoptotic gene Bcl-xL in HCC cell lines compared with a normal hepatic cell line. We also found decreased expression of the autophagic gene Beclin 1 in 44 HCC tissue samples compared with adjacent nontumor tissues. In addition, we found that the most aggressive malignant HCC cell lines and HCC tissues with recurrent disease displayed much lower autophagic levels, especially when Bcl-xL was overexpressed. Interestingly, in a tissue microarray study consisting of 300 HCC patients who underwent curative resection, the expression of Beclin 1 was only significantly correlated with disease-free survival (DFS; P &lt; 0.0001) and overall survival (OS; P &lt; 0.0001) in the Bcl-xL+ group. Multivariate and univariate analyses also revealed that Beclin 1 expression was an independent predictor for DFS and OS in Bcl-xL+ patients. In addition, we found a significant correlation between Beclin 1 expression and tumor differentiation in Bcl-xL+ but not in Bcl-xL− HCC patients. In conclusion, our data showed expression of autophagic genes and their corresponding autophagic activities were suppressed in HCC. The autophagy defects synergized with altered apoptotic activity might facilitate tumor malignant differentiation, which results in a more aggressive cancer cell phenotype and poor prognosis of HCC. [Cancer Res 2008;68(22):9167–75]
Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations
Authors: Yano Seiji , Wang Wei , Li Qi , Matsumoto Kunio , Sakurama Haruko , Nakamura Takahiro , Ogino Hirokazu , Kakiuchi Soji , Hanibuchi Masaki , Nishioka Yasuhiko , Uehara Hisanori , Mitsudomi Tetsuya , Yatabe Yasushi , Nakamura Toshikazu , Sone Saburo 
Published: November 2008

Abstract
Lung cancer with epidermal growth factor receptor (EGFR)–activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib. [Cancer Res 2008;68(22):9479–87]
“Active” Cancer Immunotherapy by Anti-Met Antibody Gene Transfer
Authors: Vigna Elisa , Pacchiana Giovanni , Mazzone Massimiliano , Chiriaco Cristina , Fontani Lara , Basilico Cristina , Pennacchietti Selma , Comoglio Paolo M. 
Published: November 2008

Abstract
Gene therapy provides a still poorly explored opportunity to treat cancer by “active” immunotherapy as it enables the transfer of genes encoding antibodies directed against specific oncogenic proteins. By a bidirectional lentiviral vector, we transferred the cDNA encoding the heavy and light chains of a monoclonal anti-Met antibody (DN-30) to epithelial cancer cells. In vitro, the transduced cells synthesized and secreted correctly assembled antibodies with the expected high affinity, inducing down-regulation of the Met receptor and strong inhibition of the invasive growth response. The inhibitory activity resulted (a) from the interference of the antibody with the Met receptor intracellular processing (“cell autonomous activity,” in cis) and (b) from the antibody-induced cleavage of Met expressed at the cell surface (“bystander effect,” in trans). The monoclonal antibody gene transferred into live animals by systemic administration or by local intratumor delivery resulted in substantial inhibition of tumor growth. These data provide proof of concept both for targeting the Met receptor and for a gene transfer–based immunotherapy strategy. [Cancer Res 2008;68(22):9176–83]
Identification of Alternative Splicing Markers for Breast Cancer
Authors: Venables Julian P. , Klinck Roscoe , Bramard Anne , Inkel Lyna , Dufresne-Martin Geneviève , Koh ChuShin , Gervais-Bird Julien , Lapointe Elvy , Froehlich Ulrike , Durand Mathieu , Gendron Daniel , Brosseau Jean-Philippe , Thibault Philippe , Lucier Jean-Francois , Tremblay Karine , Prinos Panagiotis , Wellinger Raymund J. , Chabot Benoit , Rancourt Claudine , Elela Sherif Abou 
Published: November 2008

Abstract
Breast cancer is the most common cause of cancer death among women under age 50 years, so it is imperative to identify molecular markers to improve diagnosis and prognosis of this disease. Here, we present a new approach for the identification of breast cancer markers that does not measure gene expression but instead uses the ratio of alternatively spliced mRNAs as its indicator. Using a high-throughput reverse transcription-PCR–based system for splicing annotation, we monitored the alternative splicing profiles of 600 cancer-associated genes in a panel of 21 normal and 26 cancerous breast tissues. We validated 41 alternative splicing events that significantly differed in breast tumors relative to normal breast tissues. Most cancer-specific changes in splicing that disrupt known protein domains support an increase in cell proliferation or survival consistent with a functional role for alternative splicing in cancer. In a blind screen, a classifier based on the 12 best cancer-associated splicing events correctly identified cancer tissues with 96% accuracy. Moreover, a subset of these alternative splicing events could order tissues according to histopathologic grade, and 5 markers were validated in a further blind set of 19 grade 1 and 19 grade 3 tumor samples. These results provide a simple alternative for the classification of normal and cancerous breast tumor tissues and underscore the putative role of alternative splicing in the biology of cancer. [Cancer Res 2008;68(22):9525–31]
Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate
Authors: Lewis Phillips Gail D. , Li Guangmin , Dugger Debra L. , Crocker Lisa M. , Parsons Kathryn L. , Mai Elaine , Blättler Walter A. , Lambert John M. , Chari Ravi V.J. , Lutz Robert J. , Wong Wai Lee T. , Jacobson Frederic S. , Koeppen Hartmut , Schwall Ralph H. , Kenkare-Mitra Sara R. , Spencer Susan D. , Sliwkowski Mark X. 
Published: November 2008

Abstract
HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development. [Cancer Res 2008;68(22):9280–90]