bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitumor Effects of Mucin 1/sec Involves the Modulation of Urokinase-Type Plasminogen Activator and Signal Transducer and Activator of Transcription 1 Expression in Tumor Cells
Authors: Ilkovitch Dan , Handel-Fernandez Mary Ellen , Herbert Lynn M. , Lopez Diana M. 
Published: April 2008

Abstract
Expression of the transmembrane isoform of Mucin 1 (MUC1/TM) in an aggressive murine mammary tumor line, DA-3, does not alter tumor development and metastasis, leading to death of the host. However, tumor cells expressing a secreted isoform of MUC1 (MUC1/sec) fail to develop tumors in immunocompetent mice. The rejection of MUC1/sec-expressing tumor cells is immunologically mediated, as, initially, innate cells and, ultimately, T cells are required. After gene array analysis, and confirmation at the protein level, it was discovered that MUC1/sec-expressing tumor cells (DA-3/sec) have a significant reduction in expression of urokinase-type plasminogen activator (uPA) relative to the parental tumor line and tumor cells expressing MUC1/TM. The serine protease uPA has been found to be involved in growth-promoting signaling, angiogenesis, and induction of matrix remodeling leading to metastasis. Although the tumor-promoting Stat3 transcription factor was unaltered in these tumor cells, the tumor-suppressive and IFN-responsive signal transducer and activator of transcription 1 (Stat1) is dramatically up-regulated in DA-3/sec cells. In addition, treatment of various murine and human cell lines with conditioned medium containing MUC1/sec results in up-regulation of Stat1. DA-3/sec tumor cells are also sensitized to the antiproliferative effects of IFN-γ. Furthermore, transfection of the Stat1 gene into DA-3 tumor cells leads to a down-regulation of uPA and delays tumor progression. Thus, Stat1 up-regulation in DA-3/sec cells seems to play a significant role in the mechanism(s) by which rejection of tumor cells expressing MUC1/sec may be occurring. [Cancer Res 2008;68(7):2427–35]
Immunity to Growth Factor Receptor–Bound Protein 10, a Signal Transduction Molecule, Inhibits the Growth of Breast Cancer in Mice
Authors: O-Sullivan InSug , Chopra Amla , Carr Janai , Kim Tae Sung , Cohen Edward P. 
Published: April 2008

AbstractThis study describes the application of a unique strategy to identify breast cancer antigens [tumor-associated antigen (TAA)]. In a mouse model, the strategy led to the identification of growth factor receptor–bound protein 10 (Grb10) as a newly identified TAA. Grb10 is a signal transduction molecule associated with multiple transmembrane tyrosine kinase receptors. It was discovered by comparing microarrays of cellular breast cancer vaccines highly enriched for cells that induced breast cancer immunity in tumor-bearing mice with nonenriched vaccines. The vaccines were prepared by transferring a cDNA expression library derived from SB5b cells, a breast cancer cell line C3H/He origin (H-2k), into LM mouse fibroblasts (H-2k). As the transferred cDNA integrates spontaneously into the genome of the recipient cells, replicates as the cells divide, and is expressed, the vaccine could be prepared from microgram amounts of tumor tissue. Relatively few cells in the transduced cell population, however, incorporated cDNA fragments that included genes specifying TAA. (The vast majority specified normal cellular constituents.) A unique strategy was used, therefore, to enrich the vaccine for immunotherapeutic cells. Twenty genes were overrepresented in the enriched vaccines. One, the gene for Grb10, was ∼100-fold overrepresented. To determine if Grb10 in the enriched vaccine was partly responsible for its therapeutic benefits, the gene was transferred into the fibroblast cell line, which was then used as a vaccine. Mice with established breast cancer treated solely by immunization with the modified fibroblasts developed robust immunity to the breast cancer cells, which, in some instances, was sufficient to result in tumor rejection. [Cancer Res 2008;68(7):2463–70]
Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
Authors: Rhodes Nelson , Heerding Dirk A. , Duckett Derek R. , Eberwein Derek J. , Knick Victoria B. , Lansing Timothy J. , McConnell Randy T. , Gilmer Tona M. , Zhang Shu-Yun , Robell Kimberly , Kahana Jason A. , Geske Robert S. , Kleymenova Elena V. , Choudhry Anthony E. , Lai Zhihong , Leber Jack D. , Minthorn Elisabeth A. , Strum Susan L. , Wood Edgar R. , Huang Pearl S. , Copeland Robert A. , Kumar Rakesh 
Published: April 2008

Abstract
Akt kinases 1, 2, and 3 are important regulators of cell survival and have been shown to be constitutively active in a variety of human tumors. GSK690693 is a novel ATP-competitive, low-nanomolar pan-Akt kinase inhibitor. It is selective for the Akt isoforms versus the majority of kinases in other families; however, it does inhibit additional members of the AGC kinase family. It causes dose-dependent reductions in the phosphorylation state of multiple proteins downstream of Akt, including GSK3β, PRAS40, and Forkhead. GSK690693 inhibited proliferation and induced apoptosis in a subset of tumor cells with potency consistent with intracellular inhibition of Akt kinase activity. In immune-compromised mice implanted with human BT474 breast carcinoma xenografts, a single i.p. administration of GSK690693 inhibited GSK3β phosphorylation in a dose- and time-dependent manner. After a single dose of GSK690693, &gt;3 μmol/L drug concentration in BT474 tumor xenografts correlated with a sustained decrease in GSK3β phosphorylation. Consistent with the role of Akt in insulin signaling, treatment with GSK690693 resulted in acute and transient increases in blood glucose level. Daily administration of GSK690693 produced significant antitumor activity in mice bearing established human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts. Immunohistochemical analysis of tumor xenografts after repeat dosing with GSK690693 showed reductions in phosphorylated Akt substrates in vivo. These results support further evaluation of GSK690693 as an anticancer agent. [Cancer Res 2008;68(7):2366–74]
Cell Cycle–Dependent Ciliogenesis and Cancer
Authors: Plotnikova Olga V. , Golemis Erica A. , Pugacheva Elena N. 
Published: April 2008

Abstract
In mammals, most cell types have primary cilia, protruding structures involved in sensing mechanical and chemical signals from the extracellular environment that act as major communication hubs for signaling controlling cell differentiation and polarity. The list of clinical disorders associated with ciliary dysfunction has expanded from polycystic kidney disease to include many others. Transformed cells commonly lack cilia, but whether this lack is cause or consequence of transformation is not well understood. Here we discuss work addressing recently identified actions of the cancer-promoting proteins Aurora A and HEF1/NEDD9/CAS-L at cilia. Together with older studies, this work suggests that loss of cilia in cancer may contribute to the insensitivity of cancer cells to environmental repressive signals, based in part on derangement of cell cycle checkpoints governed by cilia and centrosomes. [Cancer Res 2008;68(7):2058–61]
Effect of Caffeine on the ATR/Chk1 Pathway in the Epidermis of UVB-Irradiated Mice
Authors: Lu Yao-Ping , Lou You-Rong , Peng Qing-Yun , Xie Jian-Guo , Nghiem Paul , Conney Allan H. 
Published: April 2008

Abstract
Administration of caffeine was shown in earlier studies to enhance UVB-induced apoptosis and inhibit UVB-induced carcinogenesis in hairless SKH-1 mice. Here, we describe a potential mechanism for these in vivo effects. A single irradiation of mouse skin with UVB activated the ataxia-telangiectasia mutated– and Rad3-related (ATR) pathway, causing a severalfold increase in keratinocytes with phospho-Chk1 (Ser345) and a marked decrease in mitotic keratinocytes with cyclin B1 compared with baseline. When given in the drinking water for 1 to 2 weeks before UVB, caffeine (0.4 mg/mL) markedly inhibited the UVB-induced phosphorylation of Chk1 on Ser345 and caused premature expression of cyclin B1 in the epidermis. Normal keratinocytes had delayed mitotic entry for &gt;10 h following UVB. Caffeine administration reduced this mitotic delay to only 4 h and caused markedly increased apoptosis by 6 to 10 h after UVB. p53 knockout mice were used to determine the role of p53 in these processes. Irradiation with UVB markedly decreased the number of mitotic keratinocytes with cyclin B1 in p53 knockout mice, and topical caffeine immediately after UVB abrogated this response and increased UVB-induced apoptosis severalfold. These effects of caffeine in knockout mice were substantially greater than in wild-type mice. The ability of caffeine to promote the deletion of p53−/− keratinocytes may be relevant to its inhibitory effect on UVB-induced skin cancer. Our studies indicate that administration of caffeine enhances the removal of DNA-damaged cells by inhibiting the ATR-mediated phosphorylation of Chk1 and prematurely increasing the number of cyclin B1–containing cells that undergo lethal mitosis. [Cancer Res 2008;68(7):2523–9]
Gli Activity Correlates with Tumor Grade in Platelet-Derived Growth Factor–Induced Gliomas
Authors: Becher Oren J. , Hambardzumyan Dolores , Fomchenko Elena I. , Momota Hiroyuki , Mainwaring Lori , Bleau Anne-Marie , Katz Amanda M. , Edgar Mark , Kenney Anna M. , Cordon-Cardo Carlos , Blasberg Ron G. , Holland Eric C. 
Published: April 2008

Abstract
Gli signaling is critical for central nervous system development and is implicated in tumorigenesis. To monitor Gli signaling in gliomas in vivo, we created platelet-derived growth factor–induced gliomas in a Gli-luciferase reporter mouse. We find that Gli activation is found in gliomas and correlates with grade. In addition, we find that sonic hedgehog (SHH) is expressed in these tumors and also correlates with grade. We identify microvascular proliferation and pseudopalisades, elements that define high-grade gliomas as SHH-producing microenvironments. We describe two populations of SHH-producing stromal cells that reside in perivascular niche (PVN), namely low-cycling astrocytes and endothelial cells. Using the Ptc-LacZ knock-in mouse as a second Gli responsive reporter, we show β-galactosidase activity in the PVN and in some tumors diffusely throughout the tumor. Lastly, we observe that SHH is similarly expressed in human gliomas and note that an intact tumor microenvironment or neurosphere conditions in vitro are required for Gli activity. [Cancer Res 2008;68(7):2241–49]
Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer
Authors: Gautschi Oliver , Tepper Clifford G. , Purnell Phillip R. , Izumiya Yoshihiro , Evans Christopher P. , Green Tim P. , Desprez Pierre Y. , Lara Primo N. , Gandara David R. , Mack Philip C. , Kung Hsing-Jien 
Published: April 2008

Abstract
Deregulated activation of the Src tyrosine kinase and heightened Id1 expression are independent mediators of aggressive tumor biology. The present report implicates Src signaling as a critical regulator of Id1 gene expression. Microarray analyses showed that Id family genes were among the most highly down-regulated by incubation of A549 lung carcinoma cells with the small-molecule Src inhibitor AZD0530. Id1 transcript and protein levels were potently reduced in a dose-dependent manner concomitantly with the reduction of activated Src levels. These effects were conserved across a panel of lung, breast, prostate, and colon cancer cell lines and confirmed by the ability of PP2, Src siRNA, and Src-blocking peptides to suppress Id1 expression. PP2, AZD0530, and dominant-negative Src abrogated Id1 promoter activity, which was induced by constitutively active Src. The Src-responsive region of the Id1 promoter was mapped to a region 1,199 to 1,360 bps upstream of the translation start site and contained a Smad-binding element. Src was also required for bone morphogenetic protein-2 (BMP-2)–induced Id1 expression and promoter activity, was moderately activated by BMP-2, and complexed with Smad1/5. Conversely, Src inhibitors blocked Smad1/5 nuclear translocation and binding to the Src-responsive region of the Id1 promoter. Consistent with a role for Src and Id1 in cancer cell invasion, Src inhibitors and Id1 siRNA decreased cancer cell invasion, which was increased by Id1 overexpression. Taken together, these results reveal that Src positively interacts with the BMP-Smad-Id pathway and provide new ways for targeted inhibition of Id1. [Cancer Res 2008;68(7):2250–8]
Origins and Prevalence of the American Founder Mutation of MSH2
Authors: Clendenning Mark , Baze Mark E. , Sun Shuying , Walsh Kyle , Liyanarachchi Sandya , Fix Dan , Schunemann Victoria , Comeras Ilene , Deacon Molly , Lynch Jane F. , Gong Gordon , Thomas Brittany C. , Thibodeau Stephen N. , Lynch Henry T. , Hampel Heather , de la Chapelle Albert 
Published: April 2008

Abstract
Large germline deletions within the mismatch repair gene MSH2 account for a significant proportion (up to 20%) of all deleterious mutations of this gene which are associated with Lynch syndrome. An exons 1 to 6 deletion of MSH2, originally reported in nine families, has been associated with a founding event within the United States, which genealogic studies had previously dated to 1727, and the number of present day carriers was estimated to be 18,981. Here, we report the development of a robust multiplex PCR which has assisted in the detection of 32 new families who carry the MSH2 American Founder Mutation (AFM). By offering testing to family members, 126 carriers of the AFM have been identified. Extensive genealogic studies have connected 27 of the 41 AFM families into seven extended pedigrees. These extended families have been traced back to around the 18th century without any evidence of further convergence between them. Characterization of the genomic sequence flanking the deletion and the identification of a common disease haplotype of between 0.6 and 2.3 Mb in all probands provides evidence for a common ancestor between these extended families. The DMLE+2.2 software predicts an age of ∼500 years (95% confidence interval, 425–625) for this mutation. Taken together, these data are suggestive of an earlier founding event than was first thought, which likely occurred in a European or a Native American population. The consequences of this finding would be that the AFM is significantly more frequent in the United States than was previously predicted. [Cancer Res 2008;68(7):2145–53]
Signatures Associated with Rejection or Recurrence in HER-2/neu–Positive Mammary Tumors
Authors: Worschech Andrea , Kmieciak Maciej , Knutson Keith L. , Bear Harry D. , Szalay Aladar A. , Wang Ena , Marincola Francesco M. , Manjili Masoud H. 
Published: April 2008

AbstractWe have previously shown T-cell–mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. However, following rejection of primary tumors, a fraction of animals experienced a recurrence of a neu antigen-negative variant (ANV) of MMC (tumor evasion model) after a long latency period. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-γ and can induce apoptosis of MMC in vitro. Neu transgenic (FVBN202) mice develop spontaneous tumors and cannot reject it (tumor tolerance model). To dissect the mechanisms associated with rejection or tolerance of MMC tumors, we compared transcriptional patterns within the tumor microenvironment of MMC undergoing rejection with those that resisted it either because of tumor evasion/antigen loss recurrence (ANV tumors) or because of intrinsic tolerance mechanisms displayed by the transgenic mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. The tumor evasion model showed combined activation of Th1 and Th2 with a deviation toward Th2 and humoral immune responses that failed to achieve rejection likely because of lack of target antigen. Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3. These data provide a road map for the identification of novel biomarkers of immune responsiveness in clinical trials. [Cancer Res 2008;68(7):2436–46]
Dissection of the APCCdh1-Skp2 Cascade in Breast Cancer
Authors: Fujita Takeo , Liu Weijun , Doihara Hiroyoshi , Date Hiroshi , Wan Yong 
Published: April 2008

Abstract
Purpose: Skp2 is a subunit of the SCF ubiquitin protein ligase, which plays a vital role in the control of tumorigenesis via its regulation of G1-S transition. Deregulation of Skp2 in various types of cancers correlates with aggressive clinical behavior and poor prognosis. Recent studies suggest that cell cycle–dependent fluctuation of Skp2 is governed by APCCdh1, another important E3 ligase, thereby preventing premature entry into S phase. To assess the potential role of APCCdh1 in tumorigenesis through proteolysis of Skp2, we have dissected the APCCdh1-Skp2 cascade.
Experimental Design: We manipulated the APCCdh1-Skp2 cascade and examined its cellular behavior using both breast cancer and normal breast epithelial cells. Furthermore, applying immunohistochemistry, we analyzed the clinicopathologic significance of these molecules in patients with breast cancer.
Results: Analysis of tissue arrays indicated that the percentage of samples positive for Cdh1 in breast cancer was significantly lower compared with normal breast tissues (P = 0.004). Conversely, the percentage of samples scored as positive for Skp2 in cancer was significantly higher than in normal tissues (P &lt; 0.001). Moreover, prognostic studies revealed that relatively high levels of Cdh1 are associated with survivability in patients with breast cancer. In addition, depletion of Cdh1 by small interfering RNA in normal breast cells resulted in increased cellular proliferation, whereas knockdown of Skp2 significantly suppressed growth in breast cancer cells.
Conclusions: This study shows a correlation between Skp2 and APCCdh1 in breast cancer. Thus, Cdh1 may act as an important component in tumor suppression and could be considered as a novel biomarker in breast cancer.
Profiling of Genetic Variations in Inflammation Pathway Genes in Relation to Bladder Cancer Predisposition
Authors: Yang Hushan , Gu Jian , Lin Xin , Grossman H. Barton , Ye Yuanqing , Dinney Colin P. , Wu Xifeng 
Published: April 2008

Abstract
Purpose: Compelling evidence has indicated that inflammation plays an important role in cancer development. We sought to test the hypothesis that common sequence variants in the inflammation pathway modulate bladder cancer risk.
Experimental Design: We genotyped 59 potentially functional single nucleotide polymorphisms from 35 candidate inflammation genes in a case-control study including 635 Caucasian bladder cancer patients and 635 matched controls.
Results: The most significant finding was in the 3′-untranslated region of PTGS2 (exon10+837T&gt;C, rs5275), which was associated with a significantly reduced risk (odds ratio, 0.68; 95% confidence interval, 0.54-0.87; P = 0.002) and remained significant after multiple comparison adjustment. Consistently, the most common PTGS2 haplotype containing the common allele of exon10+837T&gt;C was associated with a significantly increased risk (odds ratio, 1.27; 95% confidence interval, 1.06-1.52; P = 0.008). In contrast, the haplotypes containing at least one variant allele of exon10+837T&gt;C were all associated with a decreased risk. In a combined analysis to assess the cumulative effects of inflammation single nucleotide polymorphisms on bladder cancer risk, we found that in the anti-inflammation pathway, but not in the proinflammation pathway, when compared with individuals with a few adverse alleles, individuals with more adverse alleles had a significantly increased risk in a dose-dependent manner (Ptrend = 0.012). To further elucidate the functional mechanism of these associations, we redefined the adverse alleles based on literature-reported functional results and found that individuals with a higher number of inflammation-enhancing alleles in the anti-inflammation pathway exhibited a greater bladder cancer risk.
Conclusions: Our results strongly suggest that common variants in inflammation genes affect bladder cancer susceptibility individually and jointly.
Evaluation of d-Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis
Authors: Vuyyuri Saleha B. , Hamstra Daniel A. , Khanna Divya , Hamilton Christin A. , Markwart Sonja M. , Campbell Kathleen C.M. , Sunkara Prasad , Ross Brian D. , Rehemtulla Alnawaz 
Published: April 2008

Abstract
Purpose: Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. d-Methionine (d-Met), the dextro-isomer of the common amino acid l-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults.
Experimental Design: We evaluated if d-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice.
Results: Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with d-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P &lt; 0.05) whereas it did not confer a similar protection on transformed tumor cells. d-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6 ± 0.15). d-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by d-Met treatment. Pharmacokinetics following administration of a liquid suspension of d-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral d-Met doses between 200 and 500 mg/kg (P &lt; 0.0003).
Conclusions: d-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of d-Met to protect from oral mucositis are warranted.