bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of the Leptin Receptor in the Immune Response in Intestinal Cancer
Authors: Aloulou Nijez , Bastuji-Garin Sylvie , Le Gouvello Sabine , Abolhassani Mohammad , Chaumette Marie Thérèse , Charachon Antoine , Leroy Karen , Sobhani Iradj 
Published: November 2008

Abstract
The incidence of colorectal cancers (CRC) may be influenced by environmental factors, including nutrition. The role of peptides regulating food intake in controlling the growth and recurrence of human tumors is controversial. Leptin, a cytokine-like peptide, regulates food intake. We investigated the expression of leptin and its receptor in 171 consecutive patients (78 female and 93 male; 71 years) with CRC. Leptin concentrations in the serum (ELISA) were determined before tumor removal. ObRb was characterized in tumors and normal homologous tissues and culture cells (HT29, HCT116, and HCT116 with a transferred chromosome 3) by using immunocytochemistry, immunohistochemistry, reverse transcription-PCR (RT-PCR), and Western blotting. Microsatellite instability (MSI) phenotype was characterized by immunohistochemistry and pentaplex PCR. mRNAs of cytokines and chemokines were quantified in tumors and in normal homologous tissues (RT-PCR) in 43 patients. Adequate statistical tests, including multivariate analysis adjusted for pathologic tumor-node-metastasis (pTNM), MSI-H, and ObRb phenotypes, were used. Higher expression of ObRb in tumors compared with the homologous normal mucosa, pTNM staging but not leptin serum level, was associated with patients' progression-free survival (PFS). Tumor ObRb phenotype and pTNM were independent predictive factors of PFS. ObRb was more strongly expressed in HCT116 cells than in HCT116-Ch3 cells as well as in MSI-H tumors than in microsatellite stability and potentially associated with efficient cytotoxic antitumoral response as assessed by immunohistochemistry and RT-PCR measurements. We suggest that leptin receptor expression in tumors is involved in adaptive immune response in sporadic colon and rectal tumors likely via MSI-H phenotype orientation. [Cancer Res 2008;68(22):9413–22]
Leptin Receptor–Related Immune Response in Colorectal Tumors: The Role of Colonocytes and Interleukin-8
Authors: Abolhassani Mohammad , Aloulou Nijez , Chaumette Marie Thérèse , Aparicio Thomas , Martin-Garcia Nadine , Mansour Hicham , Le Gouvello Sabine , Delchier Jean Charles , Sobhani Iradj 
Published: November 2008

Abstract
We have shown that ObRb, the leptin receptor, is overexpressed in colorectal cancer cells, and that this may influence the patients' outcome. We investigated colonocytes as leptin targets and characterized their pivotal role in antitumor immune response. Cytokine and chemokine mRNAs in HT29 cells were measured by targeted arrays. In vitro, normal colonocytes and human colon cancer cells (HT29, Caco-2, SW480, and HCT116) were used to investigate ObRb transduction system and cytokine releases. Animal colonocytes and CD8 splenocytes and human HT29, HCT116, and CD8+ cells from blood donors were used to investigate the lymphocyte response to the colonocytes when stimulated by leptin. Leptin-induced cytokine releases in the normal colonic mucosa and tumor growth and cytokine releases within tumors in vivo were measured in male rats and nude mice, respectively. Statistical analysis was done by Fisher's exact and Mann-Whitney U tests. Various cytokines and their receptors were produced in normal and tumoral colonocytes in response to leptin by increasing nuclear factor-κB activation. Interleukin-8 (IL-8) was the main cytokine produced in vitro. The levels of IL-8 and its receptor, CXCR1, were higher in tumors than in homologous normal mucosa. Systemic leptin enhanced the proinflammatory cytokines in normal colonocytes and in HT29 xenografted tumor colonocytes. Colonocyte-derived products after leptin treatment stimulated perforin and granzyme B expressions in normal CD8+ T cells in vitro. Leptin triggers an inflammatory response in tumor tissue by directly stimulating colonocytes, which can recruit T cytotoxic cells in the tumor microenvironment. [Cancer Res 2008;68(22):9423–32]
Hypoxia-Inducible Factor-2α Correlates to Distant Recurrence and Poor Outcome in Invasive Breast Cancer
Authors: Helczynska Karolina , Larsson Anna-Maria , Holmquist Mengelbier Linda , Bridges Esther , Fredlund Erik , Borgquist Signe , Landberg Göran , Påhlman Sven , Jirström Karin 
Published: November 2008

Abstract
Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-α subunits HIF-1α and HIF-2α in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1α is not clear-cut and that of HIF-2α is largely unknown. Using IHC analyses of HIF-1α, HIF-2α, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-α subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1α and HIF-2α protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-α protein and HIF-α and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-α subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1α and HIF-2α protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1α and HIF-2α associated to high VEGF expression. HIF-2α expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer–specific survival, whereas HIF-1α did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2α remained accumulated, whereas HIF-1α protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma. [Cancer Res 2008;68(22):9212–20]
Posttranscriptional Regulation of the Breast Cancer Susceptibility Gene BRCA1 by the RNA Binding Protein HuR
Authors: Saunus Jodi M. , French Juliet D. , Edwards Stacey L. , Beveridge Dianne J. , Hatchell Esme C. , Wagner Sarah A. , Stein Sandra R. , Davidson Andrew , Simpson Kaylene J. , Francis Glenn D. , Leedman Peter J. , Brown Melissa A. 
Published: November 2008

Abstract
BRCA1 is a breast cancer susceptibility gene that is down-regulated in a significant proportion of sporadic breast cancers. BRCA1 is posttranscriptionally regulated by RNA-binding proteins, the identities of which are unknown. HuR is an RNA binding protein implicated in posttranscriptional regulation of many genes and is overexpressed in sporadic breast cancer. To investigate the possibility that these two molecules are functionally linked in breast cancer, we performed bioinformatic analysis of the BRCA1 3′ untranslated region (UTR), RNA-protein assays with the HuR protein and the BRCA1 3′UTR, and immunohistochemical analysis of a cohort of breast tumors using antibodies against BRCA1 and HuR. Here, we describe the identification of two predicted HuR-binding sites in the BRCA1 3′UTR, one of which binds specifically to HuR. We also show that this interaction is disrupted by single nucleotide substitutions in the BRCA1 3′UTR and that endogenous HuR protein associates with BRCA1 transcripts in T47D and MCF7 breast cancer cells. Expression of ectopic HuR results in a significant decrease in BRCA1 protein expression and also BRCA1 3′UTR activity. Immunohistochemical analysis revealed that although BRCA1 and HuR expression were associated with some clinicopathologic features of the tumors, there was no statistically significant correlation between BRCA1 and HuR protein expression. These results identify the first posttranscriptional protein regulator of BRCA1 and have implications for understanding BRCA1 regulation in human breast cancer. [Cancer Res 2008;68(22):9469–78]
Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth
Authors: Cassar Lucy , Li He , Pinto Alexander Ruvantha , Nicholls Craig , Bayne Sharyn , Liu Jun-Ping 
Published: November 2008

Abstract
Telomere maintenance is critical in tumor cell immortalization. Here, we report that the cytokine bone morphogenetic protein-7 (BMP7) inhibits telomerase activity that is required for telomere maintenance in cervical cancer cells. Application of human recombinant BMP7 triggers a repression of the human telomerase reverse transcriptase (hTERT) gene, shortening of telomeres, and hTERT repression–dependent cervical cancer cell death. Continuous treatment of mouse xenograft tumors with BMP7, or silencing the hTERT gene, results in sustained inhibition of telomerase activity, shortening of telomeres, and tumor growth arrest. Overexpression of hTERT lengthens telomeres and blocks BMP7-induced tumor growth arrest. Thus, BMP7 negatively regulates telomere maintenance, inducing cervical tumor growth arrest by a mechanism of inducing hTERT gene repression. [Cancer Res 2008;68(22):9157–66]
Melanoma-Specific Memory T Cells Are Functionally Active inRetTransgenic Mice without Macroscopic Tumors
Authors: Umansky Viktor , Abschuetz Oliver , Osen Wolfram , Ramacher Marcel , Zhao Fang , Kato Masashi , Schadendorf Dirk 
Published: November 2008

AbstractWe previously reported that bone marrows of breast cancer patients contained tumor antigen–specific CD8+ T cells with central or effector memory phenotype. Using a recently developed ret transgenic mouse melanoma model, we now show that bone marrows and tumors of transgenic mice contain high frequencies of CD8+ T cells specific for the melanoma antigen tyrosinase-related protein 2 and showing mostly effector memory phenotype. Moreover, increased numbers of bone marrow tyrosinase-related protein-2–specific effector memory CD8+ T cells are also detected in transgenic animals older than 20 weeks with disseminated melanoma cells in the bone marrow and lymph nodes but showing no visible skin tumors and no further melanoma progression. After a short-term coincubation with dendritic cells generated from the bone marrow and pulsed with melanoma lysates, bone marrow memory T cells from mice without macroscopic melanomas produced IFN-γ in vitro and exerted antitumor activity in vivo after adoptive transfer into melanoma-bearing mice. Our data indicate that functionally active bone marrow–derived melanoma-specific memory T cells are detectable at the phase of microscopic tumor load, suggesting that thereby they could control disseminated melanoma cells. [Cancer Res 2008;68(22):9451–8]
OSU-03012, a Novel Celecoxib Derivative, Induces Reactive Oxygen Species–Related Autophagy in Hepatocellular Carcinoma
Authors: Gao Ming , Yeh Pei Yen , Lu Yen-Shen , Hsu Chih-Hung , Chen Kuen-Feng , Lee Wei-Chung , Feng Wen-Chi , Chen Ching-Shih , Kuo Min-Liang , Cheng Ann-Lii 
Published: November 2008

Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Systemic treatments for HCC have been largely unsuccessful. OSU-03012 is a derivative of celecoxib with anticancer activity. The mechanism of action is presumably 3-phosphoinositide–dependent kinase 1 (PDK1) inhibition. This study investigated the potential of OSU-03012 as a treatment for HCC. OSU-03012 inhibited cell growth of Huh7, Hep3B, and HepG2 cells with IC50 below 1 μmol/L. In Huh7 cells, OSU-03012 did not suppress PDK1 or AKT activity. Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay and flow cytometry analysis indicated that OSU-03012 did not induce cellular apoptosis. Instead, morphologic studies by light and electron microscopy, as well as special biological staining with monodansylcadaverine, acridine orange, and microtubule-associated protein 1 light chain 3, revealed OSU-03012–induced autophagy of Huh7 cells. This OSU-03012–induced autophagy was inhibited by 3-methyladenine. Moreover, reactive oxygen species (ROS) accumulation was detected after OSU-03012 treatment. Blocking ROS accumulation with ROS scavengers inhibited autophagy formation, indicating that ROS accumulation and subsequent autophagy formation might be a major mechanism of action of OSU-03012. Daily oral treatment of BALB/c nude mice with OSU-03012 suppressed the growth of Huh7 tumor xenografts. Electron microscopic observation indicated that OSU-03012 induced autophagy in vivo. Together, our results show that OSU-03012 induces autophagic cell death but not apoptosis in HCC and that the autophagy-inducing activity is at least partially related to ROS accumulation. [Cancer Res 2008;68(22):9348–57]
Membrane Type 1 Matrix Metalloproteinase–Mediated Stromal Syndecan-1 Shedding Stimulates Breast Carcinoma Cell Proliferation
Authors: Su Gui , Blaine Stacy A. , Qiao Dianhua , Friedl Andreas 
Published: November 2008

Abstract
Mounting evidence implicates stromal fibroblasts in breast carcinoma progression. We have recently shown in three-dimensional coculture experiments that human mammary fibroblasts stimulate the proliferation of T47D breast carcinoma cells and that this activity requires the shedding of the heparan sulfate proteoglycan syndecan-1 (Sdc1) from the fibroblast surface. The goal of this project was to determine the mechanism of Sdc1 ectodomain shedding. The broad spectrum matrix metalloproteinase (MMP) inhibitor GM6001 specifically blocked Sdc1-mediated carcinoma cell growth stimulation, pointing toward MMPs as critical enzymes involved in Sdc1 shedding. MMP-2 and membrane type 1 MMP (MT1-MMP) were the predominant MMPs expressed by the mammary fibroblasts. Fibroblast-dependent carcinoma cell growth stimulation in three-dimensional coculture was abolished by MT1-MMP expression silencing with small interfering RNA and restored either by adding recombinant MT1-MMP catalytic domain or by expressing a secreted form of Sdc1 in the fibroblasts. These findings are consistent with a model where fibroblast-derived MT1-MMP cleaves Sdc1 at the fibroblast surface, leading to paracrine growth stimulation of carcinoma cells by Sdc1 ectodomain. The relevance of MT1-MMP in paracrine interactions was further supported by coculture experiments with T47D cells and primary fibroblasts isolated from human breast carcinomas or matched normal breast tissue. Carcinoma-associated fibroblasts stimulated T47D cell proliferation significantly more than normal fibroblasts in three-dimensional coculture. Function-blocking anti–MT1-MMP antibody significantly inhibited the T47D cell growth stimulation in coculture with primary fibroblasts. In summary, these results ascribe a novel role to fibroblast-derived MT1-MMP in stromal-epithelial signaling in breast carcinomas. [Cancer Res 2008;68(22):9558–65]
Garlic Constituent Diallyl Trisulfide Prevents Development of Poorly Differentiated Prostate Cancer and Pulmonary Metastasis Multiplicity in TRAMP Mice
Authors: Singh Shivendra V. , Powolny Anna A. , Stan Silvia D. , Xiao Dong , Arlotti Julie A. , Warin Renaud , Hahm Eun-Ryeong , Marynowski Stanley W. , Bommareddy Ajay , Potter Douglas M. , Dhir Rajiv 
Published: November 2008

AbstractIdentification of agents that are nontoxic but can delay onset and/or progression of prostate cancer, which is the second leading cause of cancer-related deaths among men in the United States, is highly desirable. We now show that p.o. gavage of garlic constituent diallyl trisulfide (DATS; 1 and 2 mg/day, thrice/week for 13 weeks beginning at age 8 weeks) significantly inhibits progression to poorly differentiated prostate carcinoma and pulmonary metastasis multiplicity in transgenic adenocarcinoma of mouse prostate (TRAMP) mice without any side effects. There was a trend of a decrease in average wet weights of the urogenital tract and prostate gland in 1 and 2 mg DATS–treated mice compared with controls (∼25–46% decrease in DATS-treated mice compared with controls). The incidence and the area of the dorsolateral prostate occupied by the poorly differentiated carcinoma were significantly lower in both 1 and 2 mg DATS–treated mice compared with control mice. In addition, DATS administration resulted in a statistically significant decrease in pulmonary metastasis multiplicity compared with controls (P = 0.002). The dorsolateral prostate from DATS-treated TRAMP mice exhibited decreased cellular proliferation in association with induction of cyclinB1 and securin protein levels, and suppression of the expression of neuroendocrine marker synaptophysin. However, DATS administration did not have any appreciable effect on apoptosis induction, angiogenesis, or natural killer and dendritic cell function. In conclusion, the results of the present study show, for the first time, that DATS administration prevents progression to invasive carcinoma and lung metastasis in TRAMP mice. [Cancer Res 2008;68(22):9503–11]
A Human Antibody–Drug Conjugate Targeting EphA2 Inhibits Tumor GrowthIn vivo
Authors: Jackson Dowdy , Gooya John , Mao Shenlan , Kinneer Krista , Xu Linda , Camara Margarita , Fazenbaker Christine , Fleming Ryan , Swamynathan Sudha , Meyer Damon , Senter Peter D. , Gao Changshou , Wu Herren , Kinch Michael , Coats Steven , Kiener Peter A. , Tice David A. 
Published: November 2008

AbstractThe EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by EphA2 monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. In this report, we describe the isolation and characterization of a fully human monoclonal antibody (1C1) that selectively binds both the human and rodent EphA2 receptor. After cell binding, the antibody induces rapid tyrosine phosphorylation, internalization, and degradation of the EphA2 receptor. Because monoclonal antibodies that selectively bind tumor cells and internalize provide a vehicle for targeted delivery of cytotoxics, 1C1 was conjugated to the microtubule inhibitor monomethylauristatin phenylalanine using a stable maleimidocaproyl linker. The anti-EphA2 antibody-drug conjugate [1C1–maleimidocaproyl-MMAF (mcMMAF)] stimulated the activation of caspase-3/caspase-7 and the death of EphA2-expressing cells with IC50 values as low as 3 ng/mL. Similarly, the conjugate induced degradation of the EphA2 receptor and inhibited tumor growth in vivo. Administration of 1C1-mcMMAF at doses as low as 1 mg/kg once weekly resulted in significant growth inhibition of EphA2-expressing tumors without any observable adverse effects in mouse xenograft and rat syngeneic tumor models. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of EphA2-expressing tumors. [Cancer Res 2008;68(22):9367–74]
Small Interfering RNA Molecules Targeting Endothelin-Converting Enzyme-1 Inhibit Endothelin-1 Synthesis and the Invasive Phenotype of Ovarian Carcinoma Cells
Authors: Rayhman Oleg , Klipper Eyal , Muller Laurent , Davidson Ben , Reich Reuven , Meidan Rina 
Published: November 2008

AbstractEndothelin-1 (ET-1) has been implicated in the progression of various cancers, including ovarian carcinoma. We found that the ovarian carcinoma cell lines ES2 and OVCAR3 and tumors from different anatomic sites expressed ET-1 system members [ET receptor A and ET-converting enzyme-1 (ECE-1)]. However, only ECE-1 was significantly higher in the solid tumors compared with effusions. We therefore investigated the effect of RNA interference-induced knockdown of ECE-1, the key enzyme in ET-1 production, on these two ovarian carcinoma cell lines. Small interfering RNA (siRNA) targeting of ECE-1 markedly reduced ECE-1 mRNA and protein levels, which subsequently led to 80% to 90% inhibition of ET-1 peptide secretion by the cells. ECE-1 silencing also profoundly affected the behavior of tumor cells compared with cells treated with scrambled siRNA. Silenced cells exhibited (a) reduced ET-1–dependent p44/42 mitogen-activated protein kinase phosphorylation; (b) decreased invasiveness and matrix metalloproteinase-2 activity; (c) improved adhesion to basal lamina proteins, laminin-1, and collagen IV; and (d) increased E-cadherin, an epithelial adhesion molecule, and reduced N-cadherin expression, a mesenchymal marker. Altered cell adherence is one of the hallmarks of the transformed phenotype, often characterized by the loss of the epithelial features and the gain of a mesenchymal phenotype. ECE-1 ablation did not, however, alter viable ovarian carcinoma cell numbers. Addition of exogenous ET-1 reversed the effects cited above. Taken together, these data indicate that siRNA is an effective tool for manipulating ECE-1 expression, ET-1 biosynthesis, and invasiveness of ovarian carcinoma. ECE-1 silencing may therefore develop into a promising novel anticancer therapy. [Cancer Res 2008;68(22):9265–73]
A Novel Mechanism of Late Gene Silencing Drives SV40 Transformation of Human Mesothelial Cells
Authors: Carbone Michele , Pannuti Antonio , Zhang Lei , Testa Joseph R. , Bocchetta Maurizio 
Published: November 2008

Abstract
Suppression of the late gene expression, usually by integration of the viral DNA into the host genome, is a critical step in DNA tumor virus carcinogenesis. SV40 induces high rates of transformation in infected primary human mesothelial cells in tissue culture, leading to the formation of immortal cell lines (SV40-transformed human mesothelial cell lines, S-HML). The studies described here were designed to elucidate the unusual susceptibility of primary human mesothelial cells to SV40 carcinogenesis. We found that S-HML contained wild-type, mostly episomal SV40 DNA. In these cells, the early genes that code for the viral oncogenes are expressed; at the same time, the synthesis of the late genes, capsid proteins, is suppressed and S-HML are not lysed. Late gene suppression is achieved through the production of antisense RNA molecules. These antisense RNA molecules originate in the early region of the SV40 circular chromosome and proceed in antisense orientation into the late gene region, leading to the formation of highly unstable double-strand RNA, which is rapidly degraded. Our results reveal a novel biological mechanism responsible for the suppression of late viral gene products, an important step in viral carcinogenesis in humans. [Cancer Res 2008;68(22):9488–96]