bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tunicamycin Sensitizes Human Melanoma Cells to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis by Up-regulation of TRAIL-R2 via the Unfolded Protein Response
Authors: Jiang Chen Chen , Chen Li Hua , Gillespie Susan , Kiejda Kelly A. , Mhaidat Nizar , Wang Yu Fang , Thorne Rick , Zhang Xu Dong , Hersey Peter 
Published: June 2007

AbstractWe have reported previously low expression of death receptors for tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) in fresh isolates and tissue sections of melanoma. This seemed to correlate with relative resistance of freshly isolated melanoma cells to TRAIL-induced apoptosis. We show in this study that the endoplasmic reticulum (ER) stress inducer, tunicamycin, selectively up-regulated the cell surface expression of TRAIL-R2, but not other members of the TNF receptor family, and enhanced TRAIL-induced apoptosis in cultured melanoma cells and fresh melanoma isolates. Tunicamycin-mediated sensitization of melanoma cells to TRAIL-induced apoptosis was associated with increased activation of the caspase cascade and reduction in mitochondrial membrane potential and was inhibited by a recombinant TRAIL-R2/Fc chimeric protein. Up-regulation of TRAIL-R2 on the melanoma cell surface was associated with increased transcription of TRAIL-R2 and its total protein levels. Two signaling pathways of the ER stress-induced unfolded protein response mediated by inositol-requiring transmembrane kinase and endonuclease 1α (IRE1α) and activation of transcription factor 6 (ATF6), respectively, seemed to be involved. In one melanoma line, there was clear evidence of activation of the IRE1α pathway, and small interfering RNA (siRNA) knockdown of IRE1α substantially reduced the up-regulation of TRAIL-R2. Similarly, there was evidence for the activation of the ATF6 pathway, and siRNA knockdown of ATF6 had a delayed effect on TRAIL-R2 expression in one but not another melanoma cell line. Moreover, the transcription factor CCAAT/enhancer-binding protein homologous protein seemed to be involved in the up-regulation of TRAIL-R2 by tunicamycin, but its role varied between different melanoma lines. Taken together, our results suggest that agents that induce ER stress may enhance TRAIL-R2 expression and increase the therapeutic response to TRAIL in melanoma. [Cancer Res 2007;67(12):5880–8]
Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling
Authors: Verona Erik V. , Elkahloun Abdel G. , Yang Junhua , Bandyopadhyay Abhik , Yeh I-Tien , Sun Lu-Zhe 
Published: June 2007

Abstract
Increasing evidence points to an active stromal involvement in cancer initiation and progression. Cytokines derived from tumor cells are believed to modulate stromal cells to produce growth and angiogenic factors, which in turn provide the tumor with the necessary microenvironment for expansion and invasion. Transforming growth factor β (TGFβ) has been implicated as a candidate cytokine to mediate this communication. However, how its signaling in stromal cells regulates tumorigenesis and tumor progression remains unresolved. We show that normal, presenescent fibroblasts or prostate stromal cells cotransplanted with prostate carcinoma cells s.c. into nude mice reduced tumor latency and accelerated tumor growth. When their TGFβ signaling was blocked, the fibroblasts and stromal cells still stimulated tumor initiation but no longer supported tumor growth as control cells did. The loss of the tumor growth–promoting activity of the stromal cells with attenuated TGFβ signaling was not associated with altered cellular senescence or tumor angiogenicity. TGFβ and the medium conditioned by the prostate carcinoma cells stimulated myofibroblast differentiation of the intact stromal cells, but not the stromal cells with attenuated TGFβ signaling. Gene microarray and quantitative reverse transcription-PCR analyses showed that TGFβ up-regulated a host of genes in stromal cells that are involved in tissue remodeling and wound healing. Thus, our study provides evidence for TGFβ as a supporting agent in tumor progression through the induction of a perpetual wound healing process in the tumor microenvironment. [Cancer Res 2007;67(12):5737–46]
Haplotype Analysis of CYP11A1 Identifies Promoter Variants Associated with Breast Cancer Risk
Authors: Yaspan Brian L. , Breyer Joan P. , Cai Qiuyin , Dai Qi , Elmore J. Bradford , Amundson Isaac , Bradley Kevin M. , Shu Xiao-Ou , Gao Yu-Tang , Dupont William D. , Zheng Wei , Smith Jeffrey R. 
Published: June 2007

Abstract
The CYP11A1 gene encodes the cholesterol side chain cleavage enzyme that catalyzes the initial and rate-limiting step of steroidogenesis. A large number of epidemiologic studies have implicated the duration and degree of endogenous estrogen exposure in the development of breast cancer in women. Here, we conduct a systematic investigation of the role of genetic variation of the CYP11A1 gene in breast cancer risk in a study of 1193 breast cancer cases and 1310 matched controls from the Shanghai Breast Cancer Study. We characterize the genetic architecture of the CYP11A1 gene in a Chinese study population. We then genotype tagging polymorphisms to capture common variation at the locus for tests of association. Variants designating a haplotype encompassing the gene promoter are significantly associated with both increased expression (P = 1.6e−6) and increased breast cancer risk: heterozygote age-adjusted odds ratio (OR), 1.51 [95% confidence interval (95% CI), 1.19–1.91]; homozygote age-adjusted OR, 2.94 (95% CI, 1.22–7.12), test for trend, P = 5.0e−5. Among genes controlling endogenous estrogen metabolism, CYP11A1 harbors common variants that may influence expression to significantly modify risk of breast cancer. [Cancer Res 2007;67(12):5673–82]
Targeting the Loss of the von Hippel-Lindau Tumor Suppressor Gene in Renal Cell Carcinoma Cells
Authors: Sutphin Patrick D. , Chan Denise A. , Li James M. , Turcotte Sandra , Krieg Adam J. , Giaccia Amato J. 
Published: June 2007

Abstract
Late-stage clear cell renal carcinoma poses a formidable clinical challenge due to the high mortality rate associated with this disease. Molecular and genetic studies have identified functional loss of the von Hippel-Lindau (VHL) gene as a frequent and crucial event in the development of the malignant phenotype of clear cell renal carcinomas. Loss of VHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. The objective of this study was to evaluate the possibility of targeting VHL loss through pharmacologic means. Chromomycin A3 (ChA3) was identified through in silico analysis of existing publicly available drug profiles from the National Cancer Institute as an agent that seemed to selectively target VHL-deficient clear cell renal carcinoma cells. Genotype-selective toxicity was first determined through short-term viability assays and then confirmed with clonogenic studies. Coculture of fluorescently labeled VHL-deficient and VHL-positive cells showed discriminate killing of the VHL-deficient cells with ChA3. Mechanistically, overexpression of hypoxia-inducible factor (HIF)-2α in VHL-positive clear cell renal carcinoma cells phenocopied loss of VHL with respect to ChA3 toxicity, establishing ChA3 as a HIF-dependent cytotoxin. This study shows the feasibility of selectively targeting the loss of the VHL tumor suppressor gene in clear cell renal carcinoma for potential clinical benefit and may have greater ramifications in the development of new targeted therapies for the treatment of cancer and other genetic diseases. [Cancer Res 2007;67(12):5896–905]
Initial Analyses of Colon Cancer–Specific Antigen (CCSA)-3 and CCSA-4 as Colorectal Cancer–Associated Serum Markers
Authors: Leman Eddy S. , Schoen Robert E. , Weissfeld Joel L. , Cannon Grant W. , Sokoll Lori J. , Chan Daniel W. , Getzenberg Robert H. 
Published: June 2007

AbstractColon cancer–specific antigen (CCSA)-3 and CCSA-4 are novel colon cancer markers identified by focused proteomic analysis of nuclear structural proteins. The goal of these studies was to evaluate serum-based CCSA-3 and CCSA-4 in the detection of individuals with preneoplastic and neoplastic lesions using ELISAs. Serum samples from 107 subjects undergoing colonoscopy, 28 subjects with colorectal cancer, and 125 subjects with benign disease or other types of cancer were evaluated. Individuals who underwent colonoscopy were classified into mutually exclusive categories, including normal colon, hyperplastic polyp, nonadvanced adenoma, and advanced adenoma. Sensitivity and specificity for both CCSA-3 and CCSA-4 were evaluated using receiver operating characteristic (ROC) curves. At a cutoff of 2 μg/mL for CCSA-3 and 0.3 μg/mL for CCSA-4, each marker detected all 28 colorectal cancers, for a sensitivity of 100% (lower 95% confidence bound, 89.8%). The sensitivity for detection of the combined end point of colorectal cancer and advanced adenoma for CCSA-3 was 89.1% [95% confidence interval (95% CI), 76.4–96.4%] and for CCSA-4 was 84.8% (95% CI, 71.1–93.7%) and 91.3% (95% CI, 79.2–97.6%) for either marker positive. The specificity in individuals with normal, hyperplastic polyps, or nonadvanced adenomas was 82.0% (95% CI, 72.4–89.4%) and 91.0% (95% CI, 83.0–96.0%) for CCSA-3 and CCSA-4, respectively. ROC curves for CCSA-3 and CCSA-4 reveal an area under the curve of 0.94 (95% CI, 0.90–0.98%). In these initial analyses, CCSA-3 and CCSA-4 show promise as potential serum markers for detection of colorectal cancer and advanced adenomas. [Cancer Res 2007;67(12):5600–5]
A Novel Role for p73 in the Regulation of Akt-Foxo1a-Bim Signaling and Apoptosis Induced by the Plant Lectin, Concanavalin A
Authors: Amin A.R.M. Ruhul , Paul Rajib K. , Thakur Vijay S. , Agarwal Munna L. 
Published: June 2007

Abstract
Virtually all human cancers encounter disruption of the “p53 network.” From a therapeutic point of view, it is important to devise strategies that eliminate cancer cells, which are often defective in functional p53 and protect p53-expressing normal cells. By comparing the response of a pair of isogenic cell lines, we identify a plant-derived compound, Concanavalin A (Con A), which differentially kills p53-null cells. Further, we find that p53 family member, p73, plays a critical role that is unmasked in the absence of p53. Con A treatment leads to induction of p73 and several others that are important mediators of apoptosis and act downstream, such as p21, Bax, Foxo1a, and Bim. Inactivation of p73 reverses the expression of these proteins and apoptosis. Inhibition of Akt activation sensitizes otherwise resistant cells. These observations thus reveal a novel role for p73 in the regulation of Akt-Foxo1a-Bim signaling and apoptosis especially when p53 is absent. [Cancer Res 2007;67(12):5617–21]
Tumorigenesis in the Brain: Location, Location, Location
Authors: Gilbertson Richard J. , Gutmann David H. 
Published: June 2007

Abstract
Emerging evidence from numerous laboratories supports the notion that brain tumors arise from cells with stem cell/neuroglial progenitor cell properties (“cancer stem cells”). Two recent studies suggest that histologically similar tumors from different brain regions are molecularly distinct because they arise from distinct populations of site-restricted progenitor cells. These new findings imply an interaction between the cell of origin, the tumor microenvironment, and specific cancer-causing genetic changes in the evolution of central nervous system tumors. [Cancer Res 2007;67(12):5579–82]
LKB1 Catalytically Deficient Mutants Enhance Cyclin D1 Expression
Authors: Scott Kristine D. , Nath-Sain Suchita , Agnew Meghan D. , Marignani Paola A. 
Published: June 2007

Abstract
Mutations in the serine-threonine tumor-suppressor kinase LKB1 are responsible for Peutz-Jeghers syndrome, characterized by hamartomatous proliferation and an increased risk of developing cancer. Mutations in lkb1 have also been identified in sporadic cancers, suggesting a wider role for LKB1 in cancer that is not limited to hamartomatous polyposis syndromes. Here, we show that LKB1 catalytically deficient mutants, when introduced into DLD1p21−/−p53−/− colorectal cancer cells, allowed for progression of cells through to S phase of cell cycle and elicited the expression of Rb, cyclin E, and cyclin A2 whereas the introduction of LKB1 lead to G1 cell cycle arrest independent of p21WAF/CIP1 and/or p53 expression. Furthermore, we show that LKB1 catalytically deficient mutants activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. In addition to compromising the tumor-suppressor function of LKB1, our findings highlight an emerging role for LKB1 catalytically deficient mutants, a gain of oncogenic properties. [Cancer Res 2007;67(12):5622–7]
Inflammation-Mediated Cytosine Damage: A Mechanistic Link between Inflammation and the Epigenetic Alterations in Human Cancers
Authors: Valinluck Victoria , Sowers Lawrence C. 
Published: June 2007

Abstract
Aberrant methylation patterns have long been known to exist in the promoter regions of key regulatory genes in the DNA of tumor cells. However, the mechanisms by which these methylation patterns become altered during the transformation of normal cells to tumor cells have remained elusive. We have recently shown in in vitro studies that inflammation-mediated halogenated cytosine damage products can mimic 5-methylcytosine in directing enzymatic DNA methylation and in enhancing the binding of methyl-binding proteins whereas certain oxidative damage products inhibit both. We have therefore proposed that cytosine damage products could potentially interfere with normal epigenetic control by altering DNA-protein interactions critical for gene regulation and the heritable transmission of methylation patterns. These inflammation-mediated cytosine damage products may provide, in some cases, a mechanistic link between inflammation and cancer. [Cancer Res 2007;67(12):5583–6]
Inactivation of the Wwox Gene Accelerates Forestomach Tumor Progression In vivo
Authors: Aqeilan Rami I. , Hagan John P. , Aqeilan Haifa A. , Pichiorri Flavia , Fong Louise Y.Y. , Croce Carlo M. 
Published: June 2007

Abstract
The WWOX gene encodes a tumor suppressor spanning the second most common human fragile site, FRA16D. Targeted deletion of the Wwox gene in mice led to an increased incidence of spontaneous and ethyl nitrosourea–induced tumors. In humans, loss of heterozygosity and reduced or loss of WWOX expression has been reported in esophageal squamous cell cancers (SCC). In the present study, we examined whether inactivation of the Wwox gene might lead to enhanced esophageal/forestomach tumorigenesis induced by N-nitrosomethylbenzylamine. Wwox+/− and Wwox+/+ mice were treated with six intragastric doses of N-nitrosomethylbenzylamine and observed for 15 subsequent weeks. Ninety-six percent (25 of 26) of Wwox+/− mice versus 29% (10 of 34) of Wwox+/+ mice developed forestomach tumors (P = 1.3 × 10−7). The number of tumors per forestomach was significantly greater in Wwox+/− than in Wwox+/+ mice (3.2 ± 0.34 versus 0.47 ± 0.17; P &lt; 0.0001). In addition, 27% of Wwox+/− mice had invasive SCC in the forestomach, as compared with 0% of wild-type controls (P = 0.002). Intriguingly, forestomachs from Wwox+/− mice displayed moderately strong Wwox protein staining in the near-normal epithelium, but weak and diffuse staining in SCC in the same tissue section, a result suggesting that Wwox was haploinsufficient for the initiation of tumor development. Our findings provide the first in vivo evidence of the tumor suppressor function of WWOX in forestomach/esophageal carcinogenesis and suggest that inactivation of one allele of WWOX accelerates the predisposition of normal cells to malignant transformation. [Cancer Res 2007;67(12):5606– 10]
Nucleotide Excision Repair Pathway Genes and Oral Premalignant Lesions
Authors: Wang Yunfei , Spitz Margaret R. , Lee J. Jack , Huang Maosheng , Lippman Scott M. , Wu Xifeng 
Published: June 2007

Abstract
Purpose: Oral premalignant lesions (OPL) are associated with tobacco exposure and an increase in risk of oral cancer. Nucleotide excision repair (NER) is one of the major DNA repair pathways involved in the removal of tobacco carcinogen adducts. Polymorphisms in NER genes may cause variations in DNA repair capacity and increase susceptibility to both premalignant lesions and cancer.
Experimental Design: In this case-control study of 144 OPL patients and 288 controls, we genotyped 11 polymorphisms in 8 major NER genes, including XPA [A23G at 5′ untranslated region (UTR)], XPD (Asp312Asn, Lys751Gln), XPC (Ala499Val, Lys939Gln), XPG (His1104Asp), XPF (Pro662Ser), ERCC6 (Met1097Val, Arg1230Pro) Rad23B (Ala249Val), and CCNH (Val270Ala).
Results: We found significant or borderline-significant associations between OPL risk and the polymorphisms XPA (A23G), XPD (Lys751Gln), XPC (Ala499Val), Rad23B (Ala249Val), and XPD (Asp312Asn), with adjusted odds ratios (ORs) of 1.97 [95% confidence interval (95% CI), 1.27-3.06], 1.60 (95% CI, 1.02-2.51), 0.63 (95% CI, 0.40-1.00), 0.67 (95% CI, 0.41-1.07), and 1.42 (95% CI, 0.90-2.23), respectively. When further stratified analyses were done, the decreased risk conferred by the XPC (Ala499Val) variant allele was more evident in older individuals (OR, 0.50; 95% CI, 0.24-1.03), in women (OR, 0.46; 95% CI, 0.21-1.01), in ever smokers (OR, 0.59; 95% CI, 0.33-1.05), and in never drinkers (OR, 0.42; 95% CI, 0.18-1.00). Finally, we found joint effects between these NER gene variants and smoking status. For example, when never smokers with the XPA 23A genotypes were used as the reference group, the ORs for never smokers with the XPA 23G genotype, smokers with the 23A genotype, and smokers with 23G genotypes were 2.19 (1.07-4.46), 2.64 (1.42-4.89), and 5.04 (2.62-9.69), respectively. Gene-gene and gene-smoking interaction for OPLs risk were also confirmed by multifactor dimensionality reduction (MDR) analysis in our study. MDR analysis revealed that a model containing ever smoking, XPA (A23G), XPC (Ala499Val), and XPD (Asp312Asn) was the best model to predict OPL risk with maximum average cross-validation consistency and minimum prediction error (P &lt; 0.001).
Conclusion: Our results suggest that polymorphisms in NER genes may contribute to genetic susceptibility to OPLs and may therefore contribute to the development of oral cancer.
Human Leukocyte Antigen Class I Antigen Expression Is an Independent Prognostic Factor in Ovarian Cancer
Authors: Rolland Phil , Deen Suha , Scott Ian , Durrant Lindy , Spendlove Ian 
Published: June 2007

AbstractPurpose: Despite improvements in cancer treatment, the prognosis of ovarian cancer remains low and imperfectly predicted by traditional pathologic criteria. Biomarkers that predict prognosis independently of such criteria shed light on important molecular variations, aiding in the development and targeting of novel therapies. Previous work has shown human leukocyte antigen (HLA) class I antigen expression to be independently predictive of prognosis in colorectal and breast cancer. We investigated the prognostic potential of HLA class I antigen expression by studying a large series of ovarian cancers.Experimental Design: A tissue microarray of 339 ovarian cancer cases linked to prospectively recorded clinicopathologic and follow-up data was constructed. This was stained following a standard immunohistochemical protocol for HLA class I heavy chain (HC-10) and β2-microglobulin (β2-m). HLA class I antigen expression was compared with clinicopathologic factors and overall disease-specific survival using the Pearson χ2 test, Kaplan-Meier curves, and the log-rank test. Cox regression was used to test for the independence and magnitude of effects.Results: There were no univariate correlations between HLA class I antigen expression and clinicopathologic factors. Deviation from an HC-10+/β2-m+ phenotype correlated with reduced survival in univariate analysis (log-rank, 5.69; P = 0.017); a retained HC-10+/β2-m+ phenotype predicted improved prognosis independently of age, stage, level of cytoreduction, and chemotherapy usage on multivariate analysis (hazard ratio, 0.587; 95% confidence interval, 0.442-0.781; P &lt; 0.001).Conclusions: HLA class I antigen expression is an independent prognostic marker in ovarian cancer, its loss correlating with a poor prognostic outcome.
Treatment of Single Brain Metastasis with Resection, Intracavity Carmustine Polymer Wafers, and Radiation Therapy Is Safe and Provides Excellent Local Control
Authors: Ewend Matthew G. , Brem Steven , Gilbert Mark , Goodkin Robert , Penar Paul L. , Varia Mahesh , Cush Sharon , Carey Lisa A. 
Published: June 2007

Abstract
Purpose: To define the safety and efficacy of carmustine polymer wafers when added to a regimen of surgery and external beam radiotherapy for treatment of a single brain metastasis.
Experimental Design: Adult patients underwent craniotomy for a single brain metastasis, and carmustine polymer wafers were placed in the tumor resection cavity. Patients then received whole-brain radiotherapy and were followed for patterns of recurrence in the central nervous system, toxicity, and survival.
Results: We enrolled 25 patients with solitary brain metastases from lung (13 patients), melanoma (4 patients), breast (3 patients), and renal carcinoma (3 patients). Two patients had severe adverse events thought to be related to wafer placement, one with seizures alone, and one with seizures and subsequent respiratory compromise. Both responded to medical therapy. There were no wound infections. The local recurrence rate was surprisingly low (0%). Four patients (16%) relapsed elsewhere in the brain, and two patients (8%) relapsed in the spinal cord. Median survival was 33 weeks; 33% of patients survived 1 year, and 25% survived 2 years.
Conclusions: The addition of local chemotherapy delivered via carmustine polymer wafers to a regimen of surgical resection and external beam radiotherapy was well tolerated by patients undergoing surgery for a single brain metastasis. There were no local recurrences, suggesting that this treatment further reduced the risk of local relapse.