bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Alterations in Tumor Stroma
Authors: Eng Charis , Leone Gustavo , Orloff Mohammed S. , Ostrowski Michael C. 
Published: August 2009

Abstract
It was traditionally believed that the tumor was the seed that lay in the passive soil of the microenvironment, with the latter providing “permissive elements” for the tumor to grow and invade. Subsequently, it was recognized that both neoplasia and its microenvironment interacted as equal partners. Recent advances addressing genomic alterations in the tumor microenvironment, relevant to clinical outcome and treatment choices, are summarized. These include microenvironmental genomic alterations not only in different solid tumors, but also, rather surprisingly, in inflammatory bowel disease. These observations promise new biomarkers of prognosis and a new compartment to target therapy. [Cancer Res 2009;69(17):6759–64]
Genetic Alterations in the Phosphoinositide 3-Kinase/Akt Signaling Pathway Confer Sensitivity of Thyroid Cancer Cells to Therapeutic Targeting of Akt and Mammalian Target of Rapamycin
Authors: Liu Dingxie , Hou Peng , Liu Zhi , Wu Guojun , Xing Mingzhao 
Published: August 2009

Abstract
We investigated the genotype-dependent therapeutic potential of targeting the phosphoinositide 3-kinase (PI3K)/Akt pathway for thyroid cancer. Proliferation of TPC1, Hth7, FTC133, OCUT1, K1, and BCPAP cells that harbored PI3K/Akt-activating genetic alterations was potently inhibited by the Akt inhibitor perifosine, whereas SW1736, Hth74, WRO, KAT18, and TAD2 cells that harbored no genetic alterations had no or only modest responses. Inhibition of Akt phosphorylation by perifosine was seen in these cells. Genetic-dependent apoptosis was induced by perifosine in cells selectively tested. Similarly, potent inhibition of cell proliferation by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus occurred in virtually all the cells harboring genetic alterations, whereas modest inhibition was seen in some of the cells not harboring genetic alterations. Temsirolimus inhibited the phosphorylation of p70S6K, a substrate of mTOR. Knockdown of Akt1/2 or mTOR by shRNA approach inhibited the proliferation and colony formation of FTC133 and OCUT1 cells that harbored genetic alterations in the PI3K/Akt pathway but had no effect on SW1736 and KAT18 cells that did not. Transfection with PIK3CA mutants greatly sensitized SW1736 cells to perifosine and temsirolimus. Growth of xenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine. Thus, this work for the first time shows that genetic alterations in the PI3K/Akt pathway confer thyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR. This genotype-based targeting of the PI3K/Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for thyroid cancer and warrants further studies. [Cancer Res 2009;69(18):7311–9]
Classification of Chemotherapeutic Agents Based on Their DifferentialIn vitroEffects on Dendritic Cells
Authors: Tanaka Hiroaki , Matsushima Hironori , Mizumoto Norikatsu , Takashima Akira 
Published: August 2009

AbstractDespite the crucial roles dendritic cells (DC) play in host immunity against cancer, the pharmacologic effects of many chemotherapeutic agents have remained mostly unknown. We recently developed a DC biosensor clone by engineering the stable murine DC line XS106 to express the yellow fluorescent protein (YFP) gene under the control of interleukin (IL)-1β promoter. In this study, the resulting XS106 pIL1-YFP DC clone was used to screen 54 anticancer drugs. Each drug was tested at five concentrations (0.1–10 μmol/L) for its effects on YFP expression, cell viability, and granulocyte macrophage colony-stimulating factor–dependent growth. Our unbiased systematic screening unveiled a striking heterogeneity among the tested anticancer drugs in their effects on the three functional variables. Interestingly, 15 drugs induced significant YFP expression at subcytotoxic concentrations and were thus categorized as “DC-stimulatory” anticancer drugs. These drugs were subsequently found to induce at least one of the characteristic maturational changes in mouse bone marrow–derived DCs. For example, vinblastine, a prototypic drug of this class, induced the production of IL-1β, IL-6, and IL-12, increased surface expression of CD40, CD80, CD86, and MHC class II, and augmented T cell–stimulatory capacity of DCs. Not only do these results illustrate the differential pharmacologic effects of commonly used chemotherapeutic agents on DCs, they may also provide a conceptual framework for rationale-based selection and combination of anticancer drugs for clinical application. [Cancer Res 2009;69(17):6978–86]
Dual Therapeutic Efficacy of Vinblastine as a Unique Chemotherapeutic Agent Capable of Inducing Dendritic Cell Maturation
Authors: Tanaka Hiroaki , Matsushima Hironori , Nishibu Akiko , Clausen Björn E. , Takashima Akira 
Published: August 2009

AbstractOur recent unbiased functional screen of 54 chemotherapeutic drugs unveiled striking heterogeneity in their effects on dendritic cells (DC). Most notably, vinblastine (VBL) was found to induce phenotypic and functional maturation of DCs in vitro. Here, we sought to determine whether VBL exhibits “dual” therapeutic efficacy in living animals by directly killing tumor cells and by boosting host immunity via DC maturation. Local injection of VBL in a low dose into the skin of C57BL/6 mice induced in situ maturation of epidermal Langerhans cells. When coinjected with a model antigen, ovalbumin (OVA), VBL enhanced OVA-specific cellular and humoral immune responses. When injected directly into the OVA cDNA–transduced E.G7 tumors, VBL augmented clonal expansion of OVA-reactive CD8 T cells and CTL activities. In B16 melanoma model, intratumor VBL injection induced apoptosis of melanoma cells, phenotypic maturation of tumor-infiltrating DCs, and significant CTL activities. Although complete clearance was never achieved, growth kinetic of B16 melanoma was markedly reduced in C57BL/6 mice by intratumor VBL injection. Importantly, the same treatment was far less efficacious in immunocompromised severe combined immunodeficient mice, indicating the requirement of intact host immunity. Our results introduce a new concept that VBL may be used to design “immunostimulatory” chemotherapy regimens. [Cancer Res 2009;69(17):6987–94]
Chromobox Protein Homologue 7 Protein, with Decreased Expression in Human Carcinomas, Positively Regulates E-Cadherin Expression by Interacting with the Histone Deacetylase 2 Protein
Authors: Federico Antonella , Pallante Pierlorenzo , Bianco Mimma , Ferraro Angelo , Esposito Francesco , Monti Maria , Cozzolino Marianna , Keller Simona , Fedele Monica , Leone Vincenza , Troncone Giancarlo , Chiariotti Lorenzo , Pucci Piero , Fusco Alfredo 
Published: August 2009

Abstract
Chromobox protein homologue 7 (CBX7) is a chromobox family protein encoding a novel polycomb protein, the expression of which shows a progressive reduction, well related with the malignant grade of the thyroid neoplasias. Indeed, CBX7 protein levels decreased in an increasing percentage of cases going from benign adenomas to papillary, follicular, and anaplastic thyroid carcinomas. To elucidate the function of CBX7 in carcinogenesis, we searched for CBX7 interacting proteins by a proteomic analysis. By this approach, we identified several proteins. Among these proteins, we selected histone deacetylase 2 (HDAC2), which is well known to play a key role in neoplastic cell transformation and down-regulation of E-cadherin expression, the loss of which is a critical event in the epithelial-to-mesenchymal transition. We confirmed by coimmunoprecipitation that CBX7 physically interacts with the HDAC2 protein and is able to inhibit its activity. Then, we showed that both these proteins bind the E-cadherin promoter and that CBX7 up-regulates E-cadherin expression. Consistent with these data, we found a positive statistical correlation between CBX7 and E-cadherin expression in human thyroid carcinomas. Finally, we showed that the expression of CBX7 increases the acetylation status of the histones H3 and H4 on the E-cadherin promoter. Therefore, the ability of CBX7 to positively regulate E-cadherin expression by interacting with HDAC2 and inhibiting its activity on the E-cadherin promoter would account for the correlation between the loss of CBX7 expression and a highly malignant phenotype. [Cancer Res 2009;69(17):7079–87]
Tumor Cell-Microenvironment Interaction Models Coupled with Clinical Validation Reveal CCL2 and SNCG as Two Predictors of Colorectal Cancer Hepatic Metastasis
Authors: Hu Hai , Sun Lichao , Guo Chunguang , Liu Qian , Zhou Zhuan , Peng Liang , Pan Jian , Yu Long , Lou Jinning , Yang Zhihua , Zhao Ping , Ran Yuliang 
Published: August 2009

Abstract
Purpose: This study aimed to identify novel biological markers for the prediction of colorectal cancer liver metastasis.
Experimental Design: We established two models that mimicked the interactions between colorectal tumor cells and the liver microenvironment. From these models we established subcell lines that had an enhanced ability to metastasize to the liver. Genes that related to hepatic metastasis were screened by microarray. The candidate markers were tested by immunohistochemistry, and their predictive accuracy was assessed by the cross-validation method and an independent test set.
Results: Highly metastatic colon cancer cell sublines SW1116p21 and SW1116v3 were established from the tumor cell-microenvironment interaction models. Seven of the up-regulated genes in the sublines were selected as candidate markers for predicting metastatic potential. A total of 245 colorectal cancer samples were divided into a training set containing 117 cases and a test set containing 128 cases. In the training set, immunohistochemical analysis showed CCL2 and SNCG expression was higher in the hepatic metastasis group than in the nonmetastasis group, and was correlated with poor survival. Logistic regression analysis revealed that CCL2 and SNCG levels in primary tumors, serum carcinoembryonic antigen level, and lymph node metastasis status were the only significant (P &lt; 0.05) parameters for detecting liver metastasis. In leave-one-out-cross-validation, the two markers, when combined with clinicopathologic features, resulted in 90.5% sensitivity and 90.7% specificity for hepatic metastasis detection. In an independent test set, the combination achieved 87.5% sensitivity and 82% specificity for predicting the future hepatic metastasis of colorectal cancer.
Conclusion: Our results suggest that these models are able to mimic the interactions between colorectal cancer cells and the liver microenvironment, and may represent a promising strategy to identify metastasis-related genes. CCL2 and SNCG, combined with clinicopathologic features, may be used as accurate predictors of liver metastasis in colorectal cancer. (Clin Cancer Res 2009;15(17):5485–93)
Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma
Authors: Desbois-Mouthon Christèle , Baron Aurore , Blivet-Van Eggelpoël Marie-José , Fartoux Laetitia , Venot Corinne , Bladt Friedhelm , Housset Chantal , Rosmorduc Olivier 
Published: August 2009

AbstractPurpose: The insulin-like growth factor (IGF) signaling axis is frequently dysregulated in hepatocellular carcinoma (HCC). Therefore, we investigated whether the specific targeting of the IGF type 1 receptor (IGF-1R) might represent a new therapeutic approach for this tumor.Experimental Design: Total and phosphorylated levels of IGF-1R were measured in 21 paired samples of human HCCs and adjacent nontumoral livers using ELISA. The antineoplastic potency of a novel anti–IGF-1R antibody, AVE1642, was examined in five human hepatoma cell lines.Results: Overexpression of IGF-1R was detected in 33% of HCCs and increased activation of IGF-1R was observed in 52% of tumors. AVE1642 alone had moderate inhibitory effects on cell viability. However, its combination with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, induced supra-additive effects in all cell lines that were associated with cell cycle blockage and inhibition of AKT phosphorylation. The combination of AVE1642 with rapamycin also induced a synergistic reduction of viability and of AKT phosphorylation. Of marked interest, AVE1642 alone up-regulated the phosphorylated and total levels of HER3, the main partner of EGFR, and AVE1642-induced phosphorylation of HER3 was prevented by gefitinib. Moreover, the down-regulation of HER3 expression with siRNA reduced AKT phosphorylation and increased cell sensitivity to AVE1642.Conclusions: These findings indicate that hepatoma cells overcome IGF-1R inhibition through HER3 activation in an EGFR-dependent mechanism, and that HER3 represents a critical mediator in acquired resistance to anti-IGF-1R therapy. These results provide a strong rational for targeting simultaneously EGFR and IGF-1R in clinical trials for HCC]. (Clin Cancer Res 2009;15(17):5445–56)
Concurrent and Sequential Administration of Chemotherapy and the Mammalian Target of Rapamycin Inhibitor Temsirolimus in Human Cancer Cells and Xenografts
Authors: Fung Andrea S. , Wu Licun , Tannock Ian F. 
Published: August 2009

Abstract
Purpose: Optimal scheduling of cycle-active chemotherapy with (initially cytostatic) molecular-targeted agents is important to maximize clinical benefit. Concurrent scheduling might allow up-regulation of cell death pathways at the time of chemotherapy, whereas sequential treatments might maximize inhibition of repopulation and avoid putting tumor cells out of cycle when administering cycle-active chemotherapy. We compared the effects of concurrent and sequential administration of chemotherapy and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus (CCI-779) on tumor cells and xenografts.
Experimental Design: Human prostate cancer PC-3 and LnCaP, and human breast cancer MDA-468 cells and xenografts were treated with chemotherapy (docetaxel and 5-fluorouracil, respectively) and temsirolimus, using concurrent and sequential treatment schedules. Cell killing and repopulation were evaluated by clonogenic assays. Cell cycle analysis was done using flow cytometry. Effects on xenografts were assessed by tumor growth delay.
Results: The proliferation of all cell lines was inhibited by temsirolimus in a dose-dependent manner; PTEN negative PC-3 and mutant LnCaP cells were more sensitive than PTEN-negative MDA-468 cells. Temsirolimus inhibited cell cycle progression from G1 to S phase in all cell lines. Combined treatment had greater effects than temsirolimus or chemotherapy alone: for PC-3 and LnCaP xenografts, concurrent treatment seemed superior to sequential scheduling, whereas MDA-468 cells and xenograft tumors did not show schedule dependence.
Conclusions: Combined treatment with temsirolimus and chemotherapy had a greater therapeutic effect than monotherapy; concurrent scheduling was more effective for PC-3 and LnCaP cells and xenografts that were sensitive to temsirolimus. (Clin Cancer Res 2009;15(17):5389–95)
microRNA Profiling Identifies Cancer-Specific and Prognostic Signatures in Pediatric Malignancies
Authors: Wei Jun S. , Johansson Peter , Chen Qing-Rong , Song Young K. , Durinck Steffen , Wen Xinyu , Cheuk Adam T.C. , Smith Malcolm A. , Houghton Peter , Morton Christopher , Khan Javed 
Published: August 2009

Abstract
Purpose: microRNAs have been shown to be involved in different human cancers. We therefore have performed expression profiles on a panel of pediatric tumors to identify cancer-specific microRNAs. We also investigated if microRNAs are coregulated with their host gene.
Experimental Design: We performed parallel microRNAs and mRNA expression profiling on 57 tumor xenografts and cell lines representing 10 different pediatric solid tumors using microarrays. For those microRNAs that map to their host mRNA, we calculated correlations between them.
Results: We found that the majority of cancer types clustered together based on their global microRNA expression profiles by unsupervised hierarchical clustering. Fourteen microRNAs were significantly differentially expressed between rhabdomyosarcoma and neuroblastoma, and 8 of them were validated in independent patient tumor samples. Exploration of the expression of microRNAs in relationship with their host genes showed that the expression for 43 of 68 (63%) microRNAs located inside known coding genes was significantly correlated with that of their host genes. Among these 43 microRNAs, 5 of 7 microRNAs in the OncomiR-1 cluster correlated significantly with their host gene MIRHG1 (P &lt; 0.01). In addition, high expression of MIRHG1 was significantly associated with high stage and MYCN amplification in neuroblastoma tumors, and the expression level of MIRHG1 could predict the outcome of neuroblastoma patients independently from the current neuroblastoma risk-stratification in two independent patient cohorts.
Conclusion: Pediatric cancers express cancer-specific microRNAs. The high expression of the OncomiR-1 host gene MIRHG1 correlates with poor outcome for patients with neuroblastoma, indicating important oncogenic functions of this microRNA cluster in neuroblastoma biology. (Clin Cancer Res 2009;15(17):5560–8)
Immunohistochemical Expression of Estrogen and Progesterone Receptors Identifies a Subset of NSCLCs and Correlates with EGFR Mutation
Authors: Raso Maria G. , Behrens Carmen , Herynk Matthew H. , Liu Suyu , Prudkin Ludmila , Ozburn Natalie C. , Woods Denise M. , Tang Ximing , Mehran Reza J. , Moran Cesar , Lee J. Jack , Wistuba Ignacio I. 
Published: August 2009

Abstract
Purpose: To determine the frequency of estrogen receptor α and β and progesterone receptor protein immunohistochemical expression in a large set of non–small cell lung carcinoma (NSCLC) specimens and to compare our results with those for some of the same antibodies that have provided inconsistent results in previously published reports.
Experimental Design: Using multiple antibodies, we investigated the immunohistochemical expression of estrogen receptors α and β and progesterone receptor in 317 NSCLCs placed in tissue microarrays and correlated their expression with patients' clinicopathologic characteristics and in adenocarcinomas with EGFR mutation status.
Results: Estrogen receptors α and β were detected in the nucleus and cytoplasm of NSCLC cells; however, the frequency of expression (nucleus, 5-36% for α and 42-56% for β; cytoplasm: &lt;1-42% for α and 20-98% for β) varied among the different antibodies tested. Progesterone receptor was expressed in the nuclei of malignant cells in 63% of the tumors. Estrogen receptor α nuclear expression significantly correlated with adenocarcinoma histology, female gender, and history of never smoking (P = 0.0048 to &lt;0.0001). In NSCLC, higher cytoplasmic estrogen receptor α expression significantly correlated with worse recurrence-free survival (hazard ratio, 1.77; 95% confidence interval, 1.12, 2.82; P = 0.015) in multivariate analysis. In adenocarcinomas, estrogen receptor α expression correlated with EGFR mutation (P = 0.0029 to &lt;0.0001). Estrogen receptor β and progesterone receptor but not estrogen receptor α expressed in the normal epithelium adjacent to lung adenocarcinomas.
Conclusions: Estrogen receptor α and β expression distinguishes a subset of NSCLC that has defined clinicopathologic and genetic features. In lung adenocarcinoma, estrogen receptor α expression correlates with EGFR mutations. (Clin Cancer Res 2009;15(17):5359–68)
Longitudinal Cytokine Expression during IMRT for Prostate Cancer and Acute Treatment Toxicity
Authors: Christensen Eva , Pintilie Melania , Evans Kenneth R. , Lenarduzzi Michelle , Ménard Cynthia , Catton Charles N. , Diamandis Eleftherios P. , Bristow Robert G. 
Published: August 2009

Abstract
Purpose: Proteomic profiling of patients undergoing intensity-modulated radiotherapy (IMRT) for prostate cancer can identify unique biomarkers that reflect acute toxicity in normal tissues. Our objectives were to measure inflammatory cytokine proteins during IMRT and assess the variability of individual proteomic signatures.
Experimental Design: Forty-two patients with intermediate-risk prostate cancer were recruited as follows: group 1, definitive IMRT (78 Gy in 39 fractions, n = 22), and group 2, IMRT postprostatectomy (66 Gy in 33 fractions, n = 20). Blood/urine samples were collected at baseline and weekly during IMRT. Acute toxicity was graded weekly during radiotherapy using CTC-AE v3.0 criteria. Multiplexed immunoassays were used to quantify cytokines including granulocyte macrophage colony-stimulating factor, IFN-γ, tumor necrosis factor-α, interleukin (IL)-1α, IL-2, IL6, IL-8, IL-10, and IL-12p70.
Results: We observed positive correlations between cytokine expression between serum and plasma, but not between serum/plasma and urine. The Mann-Whitney test showed a significant increase in IFN-γ and IL-6 during IMRT (P = 0.0077, 0.0035). Increasing IL-2 and IL-1 expression were associated with increased probability of acute gastrointestinal and genitourinary toxicity, respectively.
Conclusions: Determination of radiation-response signatures is feasible using multiplexed immunoassays and is a promising predictive early biomarker of toxicity outcomes. (Clin Cancer Res 2009;15(17):5576–83)
Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody
Authors: Dewan M. Zahidunnabi , Galloway Ashley E. , Kawashima Noriko , Dewyngaert J. Keith , Babb James S. , Formenti Silvia C. , Demaria Sandra 
Published: August 2009

AbstractPurpose: This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti–CTLA-4 antibody.Experimental Design: TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a “primary” site that was irradiated and a “secondary” site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy × 1, 8 Gy × 3, or 6 Gy × 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model.Results: In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P &lt; 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P &lt; 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-γ production was proportional to the inhibition of the secondary tumor.Conclusions: Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti–CTLA-4 antibody in two preclinical carcinoma models. (Clin Cancer Res 2009;15(17):5379–88)