bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estrogen Receptor α Mediates Breast Cancer Cell Resistance to Paclitaxel through Inhibition of Apoptotic Cell Death
Authors: Sui Meihua , Huang Yi , Park Ben Ho , Davidson Nancy E. , Fan Weimin 
Published: June 2007

Abstract
Estrogen receptors (ER) are expressed in ∼65% of human breast cancer. Cumulative data from clinical trials and retrospective analyses suggest that some chemotherapeutic agents may be less effective in patients with ER-positive (ER+) tumors than those with ER-negative (ER−) tumors. Paclitaxel is an active agent used in breast cancer chemotherapy. To investigate the possible influence of ER on the therapeutic efficacy of paclitaxel and its underlying mechanism, we established several isogenic ER+ cell lines by stable transfection of ERα expression vectors into ER− breast cancer BCap37 cells. We showed that 17-β estradiol significantly reduces the overall cytotoxicity of paclitaxel in BCap37-expressing ERα but has no influence on the ER− parental cells. Further analyses indicate that expression of ERα in BCap37 cells mainly interferes with paclitaxel-induced apoptotic cell death, without affecting paclitaxel-induced microtubule bundling and mitotic arrest. Moreover, we found that the addition of ICI 182,780 (Fulvestrant), a selective ER down-regulator, could completely reverse the resistance of ER+ BCap37 cells to paclitaxel. These findings showed that ERα-mediated breast tumor cell resistance to paclitaxel was through selective inhibition of paclitaxel-induced tumor cell apoptosis. Additionally, the combination of ICI 182,780 also sensitizes MCF-7 and T47D cell lines to the treatment of paclitaxel, which further confirmed the correlation between ERα and drug resistance in ER+ tumor cells. The results obtained from this study provide useful information for understanding ER-mediated resistance to paclitaxel and possibly other antineoplastic agents. [Cancer Res 2007;67(11):5337–44]
Distinctive Features of Angiogenesis and Lymphangiogenesis Determine Their Functionality during De novo Tumor Development
Authors: Eichten Alexandra , Hyun William C. , Coussens Lisa M. 
Published: June 2007

Abstract
Blood and lymphatic vasculature are essential components of all organs, responsible for maintaining organ fluid dynamics and tissue homeostasis. Although both vessel systems are composed of similar lineages of endothelial cells whose crude functions include fluid and cell transport, each system also possesses distinctive physiologic properties, enabling their distinctive functions in tissues. The role of hematogenous vasculature and development of angiogenic blood vessels during cancer development is well established; however, the role of lymphangiogenesis and structural/functional alterations occurring within lymphatic vessels during cancer development are incompletely understood. To assess premalignant versus malignant alterations in blood and lymphatic vasculature associated with squamous epithelial skin carcinogenesis, we assessed architectural and functional features of both vascular systems using a mouse model of de novo carcinoma development. We report that, as vasculature acquires angiogenic and/or lymphangiogenic properties, angiogenic blood vessels become leaky in premalignant tissue and at peripheries of carcinomas, where enlarged lymphatic capillaries efficiently drain increased tissue fluid, thereby maintaining tissue hemodynamics. In contrast, central regions of carcinomas exhibit elevated tissue fluid levels, compressed lymphatic lumina, and decreased vascular leakage, thus indicating impaired hemodynamics within solid tumors. Together, these data support the notion that therapeutic delivery of anticancer agents is best realized in premalignant tissues and/or at the peripheries of solid tumors where hemodynamic forces support drug delivery. Strategies to normalize intratumoral hemodynamics would therefore enhance therapeutic delivery to otherwise poorly accessible central regions of solid tumors. [Cancer Res 2007;67(11):5211–20]
Docosahexaenoic Acid and Butyrate Synergistically Induce Colonocyte Apoptosis by Enhancing Mitochondrial Ca2+ Accumulation
Authors: Kolar Satya Sree N. , Barhoumi Rola , Lupton Joanne R. , Chapkin Robert S. 
Published: June 2007

Abstract
We have previously shown that butyrate, a short-chain fatty acid fiber fermentation product, induces colonocyte apoptosis via a nonmitochondrial, Fas-mediated, extrinsic pathway. Interestingly, fermentable fiber when combined with fish oil containing docosahexaenoic acid (DHA, 22:6n-3) exhibits an enhanced ability to induce apoptosis and protect against colon tumorigenesis. To determine the molecular mechanism of action, the effect of DHA and butyrate cotreatment on intracellular Ca2+ homeostasis was examined. Mouse colonocytes were treated with 50 μmol/L DHA or linoleic acid (LA) for 72 h ± butyrate (0–10 mmol/L) for the final 24 h. Cytosolic and mitochondrial Ca2+ levels were measured using Fluo-4 and Rhod-2. DHA did not alter basal Ca2+ or the intracellular inositol trisphosphate (IP3) pool after 6 h butyrate cotreatment. In contrast, at 12 and 24 h, DHA- and butyrate-treated cultures exhibited a 25% and 38% decrease in cytosolic Ca2+ compared with LA and butyrate. Chelation of extracellular Ca2+ abolished the effect of thapsigargin on the IP3-releasable Ca2+ pool. DHA and butyrate cotreatment compared with untreated cells increased the mitochondrial-to-cytosolic Ca2+ ratio at 6, 12, and 24 h by 73%, 18%, and 37%, respectively. The accumulation of mitochondrial Ca2+ preceded the onset of apoptosis. RU-360, a mitochondrial-uniporter inhibitor, abrogated mitochondrial Ca2+ accumulation and also partially blocked apoptosis in DHA and butyrate cotreated cells. Collectively, these data show that the combination of DHA and butyrate, compared with butyrate alone, further enhances apoptosis by additionally recruiting a Ca2+-mediated intrinsic mitochondrial pathway. [Cancer Res 2007;67(11):5561–8]
Expression and Functional Analysis of Human Leukocyte Antigen Class I Antigen-Processing Machinery in Medulloblastoma
Authors: Raffaghello Lizzia , Nozza Paolo , Morandi Fabio , Camoriano Marta , Wang Xinhui , Garrè Maria Luisa , Cama Armando , Basso Giuseppe , Ferrone Soldano , Gambini Claudio , Pistoia Vito 
Published: June 2007

AbstractDefects in the expression and/or function of the human leukocyte antigen (HLA) class I antigen-processing machinery (APM) components are found in many tumor types. These abnormalities may have a negative impact on the interactions of tumor cells with host's immune system and on the outcome of T cell–based immunotherapy. To the best of our knowledge, no information is available about APM component expression and functional characteristics in human medulloblastoma cells (Mb). Therefore, in the present study, we have initially compared the expression of APM components in Mb, an embryonal pediatric brain tumor with a poor prognosis, with that in noninfiltrating astrocytic pediatric tumors, a group of differentiated brain malignancies with favorable prognosis. LMP2, LMP7, calnexin, β2-microglobulin–free heavy chain (HC) and β2-microglobulin were down-regulated or undetectable in Mb lesions, but not in astrocytic tumors or normal fetal cerebellum. Two Mb cell lines (DAOI and D283) displayed similar but not superimposable defects in APM component expression as compared with primary tumors. To assess the functional implications of HLA class I APM component down-regulation in Mb cell lines, we tested their recognition by HLA class I antigen-restricted, tumor antigen (TA)–specific CTL, generated by stimulations with dendritic cells that had been transfected with Mb mRNA. The Mb cell lines were lysed by TA-specific CTL in a HLA-restricted manner. Thus, defective expression of HLA class I–related APM components in Mb cells does not impair their ability to present TA to TA-specific CTL. In conclusion, these results can contribute to optimize T cell–based immunotherapeutic strategies for Mb treatment. [Cancer Res 2007;67(11):5471–8]
Chemoresistant KM12C Colon Cancer Cells Are Addicted to Low Cyclic AMP Levels in a Phosphodiesterase 4–Regulated Compartment via Effects on Phosphoinositide 3-Kinase
Authors: McEwan David G. , Brunton Valerie G. , Baillie George S. , Leslie Nicholas R. , Houslay Miles D. , Frame Margaret C. 
Published: June 2007

Abstract
One of the major problems in treating colon cancer is chemoresistance to cytotoxic chemotherapeutic agents. There is therefore a need to devise new strategies to inhibit colon cancer cell growth and survival. Here, we show that a combination of low doses of the adenylyl cyclase activator forskolin together with the specific cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) inhibitor rolipram, but not the cAMP phosphodiesterase-3 (PDE3) inhibitor cilostamide, causes profound growth arrest of chemoresistant KM12C colon cancer cells. Low-dose forskolin causes KM12C cells to exit the cell cycle in G1 by inducing p27Kip1 and primes cells for apoptosis on addition of rolipram. The effect of the low-dose forskolin/rolipram combination is mediated by displacement of the phosphatidylinositol 3,4,5-trisphosphate/phosphoinositide 3-kinase signaling module from the plasma membrane and suppression of the Akt/protein kinase-B oncogene pathway, to which KM12C cells are addicted for growth. The cAMP and phosphoinositide 3-kinase pathways form a critical intersection in this response, and reexpression of the tumor suppressor lipid phosphatase, phosphatase and tensin homologue, which is commonly lost or mutated in colon cancer, sensitizes KM12C cells to growth inhibition by challenge with low-dose forskolin. Certain chemoresistant colon cancer cells are therefore exquisitely sensitive to subtle elevation of cAMP by a synergistic low-dose adenylyl cyclase activator/PDE4 inhibitor combination. Indeed, these cells are addicted to maintenance of low cAMP concentrations in a compartment that is regulated by PDE4. Well-tolerated doses of PDE4 inhibitors that are already in clinical development for other therapeutic indications may provide an exciting new strategy for the treatment of colon cancer. [Cancer Res 2007;67(11):5248–57]
ACTIBIND, a T2 RNase, Competes with Angiogenin and Inhibits Human Melanoma Growth, Angiogenesis, and Metastasis
Authors: Schwartz Betty , Shoseyov Oded , Melnikova Vladislava O. , McCarty Marya , Leslie Michael , Roiz Levava , Smirnoff Patricia , Hu Guo-fu , Lev Dina , Bar-Eli Menashe 
Published: June 2007

Abstract
Melanoma is a very aggressive and highly angiogenic tumor in which standard treatments have had only limited success. Patients with advanced disease have a 5-year survival rate of 5%. In search for alternatives, we identified a natural product extracted from the fungus Aspergillus niger, termed ACTIBIND, that inhibits tumor growth and metastasis of melanoma in vivo. ACTIBIND, a T2 RNase, exerts antitumorigenic and antiangiogenic activities by competing with the angiogenic factor angiogenin (itself an RNase homologue). Thus, there was decreased expression and activity of the matrix metalloproteinase 2 in melanoma and vascular endothelial cells, decreased vascularization, and increased tumor cell apoptosis in vivo. ACTIBIND significantly inhibited angiogenesis in an in vivo angiogenesis assay with sponges containing angiogenin. In vitro, ACTIBIND was internalized by both melanoma and human umbilical vein endothelial cells, reached the cell nuclei, and inhibited the activity of angiogenin response elements in a dose-dependent manner. Collectively, our data indicate that ACTIBIND should be tested for its potential as a new antiangiogenic modality for the treatment of melanoma. [Cancer Res 2007;67(11):5258–66]
Mainstream Tobacco Smoke Causes Paternal Germ-Line DNA Mutation
Authors: Yauk Carole L. , Berndt M. Lynn , Williams Andrew , Rowan-Carroll Andrea , Douglas George R. , Stämpfli Martin R. 
Published: June 2007

Abstract
Despite the presence of known mutagens and carcinogens in cigarette smoke, there is currently no evidence to show that smoking, or exposure to cigarette smoke, can result in heritable genetic mutation. We show that male mice exposed to mainstream tobacco smoke (MTS) exhibit a significant increase in germ-line mutation frequency in spermatogonial stem cells. We exposed mature male mice to MTS for 6 or 12 weeks and investigated mutations arising in exposed spermatogonial stem cells at the expanded simple tandem repeat locus Ms6-hm. A generalized score test showed a significant treatment effect (P = 0.0214). Ms6-hm mutation frequency was 1.4 and 1.7 times higher in mice exposed to MTS for 6 and 12 weeks, respectively, compared with sham controls. The data suggest that mutations accumulate in the spermatogonial stem cells with extended exposures. Mutation spectra were identical between exposed and sham individuals, supporting the hypothesis that tandem repeat mutations arise through indirect mechanisms of mutation. Mutations in sperm that are passed on to offspring cause permanent, irreversible changes in genetic composition and can persist in future generations. Our research suggests that the consequences of smoking extend beyond the smoker to their nonsmoking descendents. [Cancer Res 2007;67(11):5103–4]
Insertional Mutagenesis Reveals Progression Genes and Checkpoints in MYC/Runx2 Lymphomas
Authors: Stewart Monica , Mackay Nancy , Hanlon Linda , Blyth Karen , Scobie Linda , Cameron Ewan , Neil James C. 
Published: June 2007

Abstract
In this study, we have exploited the power of insertional mutagenesis to elucidate tumor progression pathways in mice carrying two oncogenes (MYC/Runx2) that collaborate to drive early lymphoma development. Neonatal infection of these mice with Moloney murine leukemia virus resulted in accelerated tumor onset with associated increases in clonal complexity and lymphoid dissemination. Large-scale analysis of retroviral integration sites in these tumors revealed a profound bias towards a narrow range of target genes, including Jdp2 (Jundm2), D cyclin, and Pim family genes. Remarkably, direct PCR analysis of integration hotspots revealed that every progressing tumor consisted of multiple clones harboring hits at these loci, giving access to large numbers of independent insertion events and uncovering the contrasting mutagenic mechanisms operating at each target gene. Direct PCR analysis showed that high-frequency targeting occurs only in the tumor environment in vivo and is specific for the progression gene set. These results indicate that early lymphomas in MYC/Runx2 mice remain dependent on exogenous growth signals, and that progression can be achieved by constitutive activation of pathways converging on a cell cycle checkpoint that acts as the major rate-limiting step for lymphoma outgrowth. [Cancer Res 2007;67(11):5126–33]
X Inactive–Specific Transcript RNA Coating and Genetic Instability of the X Chromosome in BRCA1 Breast Tumors
Authors: Vincent-Salomon Anne , Ganem-Elbaz Carine , Manié Elodie , Raynal Virginie , Sastre-Garau Xavier , Stoppa-Lyonnet Dominique , Stern Marc-Henri , Heard Edith 
Published: June 2007

Abstract
Identification among breast tumors of those arising in a hereditary BRCA1 context remains a medical challenge. Abnormalities in X chromosome copy number and in the epigenetic stability of the inactive X chromosome (Xi) have been proposed to characterize BRCA1 breast tumors. In particular, it has been proposed that loss of BRCA1 function can lead to loss of X inactive–specific transcript (XIST) RNA association with the Xi. However, few studies have addressed this issue in a sufficiently large series of BRCA1 primary tumors. Here we assess X-chromosome status using single-cell (RNA and DNA fluorescence in situ hybridization) and global genomic (array-comparative genomic hybridization and allelotyping) approaches on a series of 11 well-defined BRCA1 tumors. We show that many or most cells of the tumors contain one or more XIST RNA domains. Furthermore, the number of XIST RNA domains per cell varied considerably even within a single tumor. Frequent X-chromosome allelic and copy number aberrations were found, in agreement with aberrant XIST RNA domain numbers. In summary, by combining multiple approaches to assess the genetics and epigenetics of a large series of BRCA1 primary tumors, we can conclude definitively that BRCA1 is not required for XIST RNA coating of the X chromosome. The intratumoral and intertumoral variability in XIST RNA domain number in BRCA1 tumors correlates with chromosomal genetic abnormalities, including gains, losses, reduplications, and rearrangements of the X-chromosome. Finally, we also show the necessity for combined global and single-cell approaches in the assessment of tumors with such a high degree of heterogeneity. [Cancer Res 2007;67(11):5134–40]
Methylation and Silencing of Protein Tyrosine Phosphatase Receptor Type O in Chronic Lymphocytic Leukemia
Authors: Motiwala Tasneem , Majumder Sarmila , Kutay Huban , Smith David Spencer , Neuberg Donna S. , Lucas David M. , Byrd John C. , Grever Michael , Jacob Samson T. 
Published: June 2007

Abstract
Purpose: Previous studies in our laboratory have shown the progressive methylation and suppression of the gene encoding protein tyrosine phosphatase, PTPRO, in the livers of rats fed a methyl-deficient diet that induces hepatocarcinogenesis. Subsequently, we observed the methylation of PTPRO in primary human lung tumors and also showed its potential tumor suppressor characteristics. The present study was undertaken to investigate whether the truncated form of PTPRO (PTPROt), specifically expressed in naïve B lymphocytes, was also methylated and suppressed in chronic lymphocytic leukemia (CLL), a disease generally affecting B lymphocytes.
Experimental Design and Results: Initial screening showed that 60% of the 52 CLL samples analyzed using methylation-specific PCR assay were methylated compared with B lymphocytes from normal individuals, which were not methylated. The expression of PTPROt, as measured by semiquantitative reverse transcription-PCR, inversely correlated with methylation in the few samples tested. Analysis of additional samples (n = 50) by combined bisulfite restriction analysis showed that the PTPRO CpG island was methylated in 82% of patients with CLL compared with B lymphocytes from normal individuals. Furthermore, overall expression of PTPRO was reduced in CLL relative to normal lymphocytes. The PTPRO gene was also suppressed by methylation in the CLL cell line WaC3CD5, where it could be reactivated upon treatment with the DNA hypomethylating agent 5-AzaC. Ectopic expression of PTPROt in a nonexpressing cell line increased growth inhibition with fludarabine treatment, a therapy commonly used for CLL.
Conclusion: This study reveals the potential role of PTPRO methylation and silencing in CLL tumorigenesis and also provides a novel molecular target in the epigenetic therapy.
Identification and Characterization of T-Cell Epitopes Deduced from RGS5, a Novel Broadly Expressed Tumor Antigen
Authors: Boß Cristina N. , Grünebach Frank , Brauer Katharina , Häntschel Maik , Mirakaj Valbona , Weinschenk Toni , Stevanovic Stefan , Rammensee Hans-Georg , Brossart Peter 
Published: June 2007

Abstract
Purpose: Identification of tumor-associated antigens and advances in tumor immunology resulted in the development of vaccination strategies to treat patients with malignant diseases. In a novel experimental approach that combined comparative mRNA expression analysis of defined cell types with the characterization of MHC ligands by mass spectrometry, we found that regulator of G protein signaling 5 (RGS5) is extensively up-regulated in a broad variety of malignant cells, and we identified two HLA-A2– and HLA-A3–binding peptides derived from the RGS5 protein. Interestingly, RGS5 was recently shown to be involved in tumor angiogenesis.
Experimental Design: We used monocyte-derived dendritic cells pulsed with these novel antigenic peptides or transfected with RGS5-mRNA for the in vitro induction of CTLs, generated from healthy donors, to analyze the presentation of RGS5-deduced epitopes by malignant cells.
Results: The generated CTL lines elicited an antigen-specific and HLA-restricted cytolytic activity against tumor cells endogenously expressing the RGS5 protein. Furthermore, we were able to induce RGS5-specific CTLs using peripheral blood mononuclear cells from a patient with acute myeloid leukemia capable of recognizing the autologous leukemic blasts while sparing nonmalignant cells.
Conclusions: These results indicate that the RGS5 peptides represent interesting candidates for the development of cancer vaccines designed to target malignant cells and tumor vessels.
Scheduling of Radiation with Angiogenesis Inhibitors Anginex and Avastin Improves Therapeutic Outcome via Vessel Normalization
Authors: Dings Ruud P.M. , Loren Melissa , Heun Hanke , McNiel Elizabeth , Griffioen Arjan W. , Mayo Kevin H. , Griffin Robert J. 
Published: June 2007

AbstractPurpose: To test whether a direct antiangiogenic peptide (anginex) and a vascular endothelial growth factor antibody (bevacizumab, Avastin) can transiently normalize vasculature within tumors to improve oxygen delivery, alleviate hypoxia, and increase the effect of radiation therapy.Experimental Design: Tumor oxygenation levels, microvessel density and pericyte coverage were monitored in three different solid tumor models (xenograft human ovarian carcinoma MA148, murine melanoma B16F10, and murine breast carcinoma SCK) in mice. Multiple treatment schedules were tested in these models to assess the influence on the effect of radiation therapy.Results: In all three tumor models, we found that tumor oxygenation levels, monitored daily in real time, were increased during the first 4 days of treatment with both anginex and bevacizumab. From treatment day 5 onward, tumor oxygenation in treated mice decreased significantly to below that in control mice. This “tumor oxygenation window” occurred in all three tumor models varying in origin and growth rate. Moreover, during the treatment period, tumor microvessel density decreased and pericyte coverage of vessels increased, supporting the idea of vessel normalization. We also found that the transient modulation of tumor physiology caused by either antiangiogenic therapy improved the effect of radiation treatment. Tumor growth delay was enhanced when single dose or fractionated radiotherapy was initiated within the tumor oxygenation window as compared with other treatment schedules.Conclusions: The results are of immediate translational importance because the clinical benefits of bevacizumab therapy might be increased by more precise treatment scheduling to ensure radiation is given during periods of peak radiosensitivity. The oxygen elevation in tumors by non–growth factor–mediated peptide anginex suggests that vessel normalization might be a general phenomenon of agents directed at disrupting the tumor vasculature by a variety of mechanisms.