bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of Gastric Tumors in ApcMin/+ Mice by the Activation of the β-Catenin/Tcf Signaling Pathway
Authors: Tomita Hiroyuki , Yamada Yasuhiro , Oyama Takeru , Hata Kazuya , Hirose Yoshinobu , Hara Akira , Kunisada Takahiro , Sugiyama Yasuyuki , Adachi Yosuke , Linhart Heinz , Mori Hideki 
Published: May 2007

Abstract
Although several lines of evidence suggest the involvement of the Wnt pathway in the development of gastric cancers, the functional significance of the pathway in gastric carcinogenesis is still poorly defined. To examine the role of the Apc/β-catenin signaling pathway in the development of gastric cancers, we investigated the gastric mucosa of the ApcMin/+ mouse, which is a murine model for familial adenomatous polyposis, carrying a germ-line mutation at codon 850 of Apc. We found that aged ApcMin/+ mice spontaneously develop multiple tumors in the stomach, which are accompanied by loss of heterozygosity of Apc. Such tumors consisted of adenomatous glands with strong nuclear accumulation of β-catenin. Even a single adenomatous gland already showed nuclear accumulation of β-catenin, suggesting that Apc/β-catenin pathway is an initiating event in gastric tumorigenesis in ApcMin/+ mice. Myc and cyclin D1 expressions, which are transcriptional targets of β-catenin/Tcf, increased in the adenomatous lesions. Furthermore, β-catenin/Tcf reporter transgenic mice with ApcMin allele showed higher levels of the transcriptional activity of β-catenin/Tcf in the gastric tumors. We also treated ApcMin/+ and wild-type mice with N-methyl-N-nitrosourea (MNU), an alkylating agent that induces adenomas and adenocarcinomas in the stomach. Consequently, MNU-treated ApcMin/+ mice significantly enhanced the tumor development in comparison with ApcMin/+ mice or MNU-treated wild-type mice. Several gastric tumors in MNU-treated ApcMin/+ mice showed invasion into the submucosal layer. These results indicate that the Apc/β-catenin pathway may play an important role in at least subset of gastric carcinomas. In addition, ApcMin/+ mice combined with MNU could be a useful short-term model to investigate multistage carcinogenesis in the stomach. [Cancer Res 2007;67(9):4079–87]
A Gynecologic Oncology Group Study of Platinum-DNA Adducts and Excision Repair Cross-Complementation Group 1 Expression in Optimal, Stage III Epithelial Ovarian Cancer Treated with Platinum-Taxane Chemotherapy
Authors: Darcy Kathleen M. , Tian Chunqiao , Reed Eddie 
Published: May 2007

Abstract
To determine whether platinum-DNA adducts and/or mRNA expression of the excision nuclease excision repair cross-complementation group 1 (ERCC1) from peripheral blood leukocytes (PBL) were associated with clinical outcome in women with epithelial ovarian cancer (EOC), participants that had previously untreated, optimally resected, stage III EOC were randomized to paclitaxel plus cisplatin or carboplatin. DNA and RNA were extracted from PBLs collected 20 to 28 h post–drug infusion. DNA adducts were measured by atomic absorption spectroscopy. ERCC1 expression was evaluated by reverse transcription-PCR. There were 170 cases fully evaluable for DNA adducts and ERCC1 mRNA expression. Adduct levels ranged from 0.43 to 131 fmol platinum/μg DNA in 140 samples; and adducts were not detectable in 30 samples. ERCC1 mRNA was detectable in 132 samples and undetectable in 38. ERCC1 mRNA expression in PBLs was not associated with any clinical end point measured. The presence of detectable versus undetectable adducts was associated with longer median progression-free survival (20.4 versus 15.6 months; P = 0.084) and overall survival (60.3 versus 36.3 months; P = 0.029), respectively. Unadjusted Cox regression modeling indicated a trend toward a reduced risk of disease progression [hazard ratio (HR), 0.686; 95% confidence interval (95% CI), 0.447–1.054; P = 0.086] and a statistically significant reduction in the risk of death (HR, 0.607; 95% CI, 0.385–0.958; P = 0.032) for women with detectable versus undetectable adducts. After adjusting for clinicopathologic variables, detectable adducts were not an independent predictor of progression-free survival or overall survival. The presence of platinum-DNA adducts, but not ERCC1 mRNA expression, in PBLs was associated with better survival, but was not an independent predictor of clinical outcome in optimal advanced EOC. [Cancer Res 2007;67(9):4474–81]
Regression of Lung and Colon Cancer Xenografts by Depleting or Inhibiting RLIP76 (Ral-Binding Protein 1)
Authors: Singhal Sharad S. , Singhal Jyotsana , Yadav Sushma , Dwivedi Seema , Boor Paul J. , Awasthi Yogesh C. , Awasthi Sanjay 
Published: May 2007

AbstractRal-binding protein 1 (RALBP1) is a stress-responsive and stress-protective multispecific transporter of glutathione conjugates (GS-E) and xenobiotic toxins. It is frequently overexpressed in malignant cells and plays a prominent antiapoptotic role selectively in cancer cells through its ability to control cellular concentration of proapoptotic oxidized lipid byproducts. In the absence of chemotherapy, depletion or inhibition of RALBP1 causes regression of syngeneic mouse B16 melanoma. Because RALBP1 transports anthracycline and Vinca alkaloid drugs, as well as GS-E, and because it confers resistance to these drugs, we proposed that depletion or inhibition of RALBP1 should cause regression of human solid tumors that overexpress RALBP1 and augment chemotherapy efficacy. Non–small-cell lung cancer (NSCLC) H358 and H520 and colon SW480 cell lines were used. Cytotoxic synergy between anti-RALBP1 immunoglobulin G (IgG), cis-diammine-dichloroplatinum (II) [CDDP], and vinorelbine was examined in cell culture and xenografts of NSCLC cells. Effects of RALBP1 depletion by antisense were examined in xenografts of NSCLC H358, NSCLC H520, and colon SW480 cells. RALBP1 depletion by phosphorothioate antisense was confirmed and was associated with rapid, complete, and sustained remissions in established s.c. human lung and colon xenografts. RALBP1 inhibition by anti-RALBP1 IgG was equally as effective as antisense and enhanced CDDP-vinorelbine in lung cancer xenografts. These studies show that RALBP1 is a transporter that serves as a key effector function in cancer cell survival and is a valid target for cancer therapy, and confirm that inhibitory modulation of RALBP1 transport activity at the cell surface is sufficient for antitumor effects. [Cancer Res 2007;67(9):–9] [Cancer Res 2007;67(9):4382–9]
Identification of Ras-Related Nuclear Protein, Targeting Protein for Xenopus Kinesin-like Protein 2, and Stearoyl-CoA Desaturase 1 as Promising Cancer Targets from an RNAi-Based Screen
Authors: Morgan-Lappe Susan E. , Tucker Lora A. , Huang Xiaoli , Zhang Qian , Sarthy Aparna V. , Zakula Dorothy , Vernetti Lawrence , Schurdak Mark , Wang Jieyi , Fesik Stephen W. 
Published: May 2007

Abstract
To identify new candidate cancer drug targets, we used RNAi as a tool to functionally evaluate genes that play a role in maintaining human tumor cell survival. We screened a small interfering RNA (siRNA) library directed against ∼3,700 individual genes to assess the ability of siRNAs to induce cell death in an in vitro cell cytotoxicity assay. We found that siRNAs specifically targeting ras-related nuclear protein (Ran), targeting protein for Xenopus kinesin-like protein 2 (TPX2), and stearoyl-CoA desaturase 1 (SCD1), significantly reduced the survival of multiple human tumor cell lines. Further target validation studies revealed that treatment with Ran and TPX2 siRNAs differentially reduced the survival of activated K-Ras–transformed cells compared with their normal isogenic counterparts in which the mutant K-Ras gene had been disrupted (DKS-8). Knockdown of Ran and TPX2 in activated mutant K-Ras cells selectively induced S-phase arrest or transient G2-M arrest phenotypes, respectively, that preceded apoptotic cell death. Given our observations that Ran and TPX2 depletion preferentially reduces the survival of activated K-Ras–transformed cells, these two proteins may serve as useful anticancer targets in tumors expressing the activated K-Ras oncogene. [Cancer Res 2007;67(9):4390–7]
A Laminin-Collagen Complex Drives Human Epidermal Carcinogenesis through Phosphoinositol-3-Kinase Activation
Authors: Waterman Elizabeth A. , Sakai Noriyasu , Nguyen Ngon T. , Horst Basil A.J. , Veitch Dallas P. , Dey Clara N. , Ortiz-Urda Susana , Khavari Paul A. , Marinkovich M. Peter 
Published: May 2007

Abstract
Laminin-332 (formerly laminin-5) and collagen VII are basement membrane proteins expressed at the invasive front of human squamous cell carcinoma (SCC) tumors. These proteins have protumorigenic properties, but whether laminin-332 and collagen VII promote SCC tumors by providing adhesion or other nonadhesive extracellular cues, or whether laminin-332 and collagen VII interact together in this process remains unknown. In this study, we examined the role of these molecules by a structural approach using an in vivo model of human SCC tumorigenesis. Here, we show that individual domains (VI and V-III) on the laminin-332 β3 chain provide distinct and highly divergent cell adhesion and tumor-promoting functions. We found that laminin β3 domain VI provided a critical role in the assembly of stable adhesion complexes, but this domain was not required in SCC tumors. Instead, we found that laminin β3 domain V-III played an essential role in SCC carcinogenesis/invasion through binding to collagen VII, which in turn, led to phosphoinositol-3-kinase activation and protection from apoptosis. Overexpression of constitutively active p110 phosphoinositol-3-kinase subunit was sufficient to restore invasion and tumorigenesis in transformed cells lacking laminin-332/collagen VII interaction in a manner independent of cellular adhesion. These studies show distinctive adhesive and signaling functions in individual domains of laminin-332, one which is required for normal epithelial adhesion and one which is required for SCC tumorigenesis. This uncoupling of stable adhesion from tumor progression in our studies suggests that laminin-332/collagen VII interaction promotes epidermal carcinogenesis through signaling rather than adhesion. [Cancer Res 2007;67(9):4264–70]
Regulation of Breast Cancer Response to Chemotherapy by Fibulin-1
Authors: Pupa Serenella M. , Giuffré Sarah , Castiglioni Fabio , Bertola Lorenzo , Cantú Marco , Bongarzone Italia , Baldassari Paola , Mortarini Roberta , Argraves W. Scott , Anichini Andrea , Menard Sylvie , Tagliabue Elda 
Published: May 2007

Abstract
Doxorubicin treatment was found to augment the expression of the extracellular matrix (ECM) protein fibulin-1 in cultured human breast cancer cell lines and in MDA-MB-361 tumors grown in athymic mice. Doxorubicin was also found to augment tumor expression of the fibulin-1–binding proteins fibronectin and laminin-1. Growth of breast cancer cell lines on Matrigel, an ECM extract containing fibulin-1 and laminin-1, resulted in lower levels of doxorubicin-induced apoptosis as compared with controls. Moreover, tumors formed by injection of athymic mice with MDA-MB-361 cells mixed with Matrigel were significantly more doxorubicin resistant and displayed lower levels of apoptosis compared with those that formed in the absence of Matrigel. Monoclonal antibodies against fibulin-1 reversed Matrigel-dependent doxorubicin resistance. Furthermore, small interfering RNA–mediated suppression of fibulin-1 expression in breast cancer cells resulted in a 10-fold increase in doxorubicin sensitivity as compared with control cells. Together, these findings point to a role for fibulin-1 in breast cancer chemoresistance. [Cancer Res 2007;67(9):4271–7]
Prostaglandin E2 Promotes Tumor Progression by Inducing Myeloid-Derived Suppressor Cells
Authors: Sinha Pratima , Clements Virginia K. , Fulton Amy M. , Ostrand-Rosenberg Suzanne 
Published: May 2007

AbstractA causative relationship between chronic inflammation and cancer has been postulated for many years, and clinical observations and laboratory experiments support the hypothesis that inflammation contributes to tumor onset and progression. However, the precise mechanisms underlying the relationship are not known. We recently reported that the proinflammatory cytokine, interleukin-1β, induces the accumulation and retention of myeloid-derived suppressor cells (MDSC), which are commonly found in many patients and experimental animals with cancer and are potent suppressors of adaptive and innate immunity. This finding led us to hypothesize that inflammation leads to cancer through the induction of MDSC, which inhibit immunosurveillance and thereby allow the unchecked persistence and proliferation of premalignant and malignant cells. We now report that host MDSC have receptors for prostaglandin E2 (PGE2) and that E-prostanoid receptor agonists, including PGE2, induce the differentiation of Gr1+CD11b+ MDSC from bone marrow stem cells, whereas receptor antagonists block differentiation. BALB/c EP2 knockout mice inoculated with the spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma have delayed tumor growth and reduced numbers of MDSC relative to wild-type mice, suggesting that PGE2 partially mediates MDSC induction through the EP2 receptor. Treatment of 4T1-tumor–bearing wild-type mice with the cyclooxygenase 2 inhibitor, SC58236, delays primary tumor growth and reduces MDSC accumulation, further showing that PGE2 induces MDSC and providing a therapeutic approach for reducing this tumor-promoting cell population. [Cancer Res 2007;67(9):4507–13]
Divergent Mechanisms of Glucocorticoid Resistance in Experimental Models of Pediatric Acute Lymphoblastic Leukemia
Authors: Bachmann Petra S. , Gorman Rosemary , Papa Rachael A. , Bardell Jane E. , Ford Jette , Kees Ursula R. , Marshall Glenn M. , Lock Richard B. 
Published: May 2007

AbstractCell line models of glucocorticoid resistance in childhood acute lymphoblastic leukemia (ALL) almost invariably exhibit altered glucocorticoid receptor (GR) function. However, these findings are incongruous with those using specimens derived directly from leukemia patients, in which GR alterations are rarely found. Consequently, mechanisms of glucocorticoid resistance in the clinical setting remain largely unresolved. We present a novel paradigm of glucocorticoid resistance in childhood ALL, in which patient biopsies have been directly established as continuous xenografts in immune-deficient mice, without prior in vitro culture. We show that the GRs from six highly dexamethasone-resistant xenografts (in vitro IC50 &gt;10 μmol/L) exhibit no defects in ligand-induced nuclear translocation and binding to a consensus glucocorticoid response element (GRE). This finding contrasts with five commonly used leukemia cell lines, all of which exhibited defective GRE binding. Moreover, whereas the GRs of dexamethasone-resistant xenografts were transcriptionally active, as assessed by the ability to induce the glucocorticoid-induced leucine zipper (GILZ) gene, resistance was associated with failure to induce the bim gene, which encodes a proapoptotic BH3-only protein. Furthermore, the receptor tyrosine kinase inhibitor, SU11657, completely reversed dexamethasone resistance in a xenograft expressing functional GR, indicating that pharmacologic reversal of glucocorticoid resistance in childhood ALL is achievable. [Cancer Res 2007;67(9):4482–90]
Relaxin-Expressing, Fiber Chimeric Oncolytic Adenovirus Prolongs Survival of Tumor-Bearing Mice
Authors: Ganesh Shanthi , Gonzalez Edick Melissa , Idamakanti Neeraja , Abramova Marina , VanRoey Melinda , Robinson Michael , Yun Chae-Ok , Jooss Karin 
Published: May 2007

Abstract
Selective replication of oncolytic viruses in tumor cells provides a promising approach for the treatment of human cancers. One of the limitations observed with oncolytic viruses currently used in the treatment of solid tumors is the inefficient spread of virus throughout the tumor mass following intratumoral injection. Data are presented showing that oncolytic adenoviruses expressing the relaxin gene and containing an Ad5/Ad35 chimeric fiber showed significantly enhanced transduction and increased virus spread throughout the tumor when compared with non–relaxin-expressing, Ad5-based viruses. The increased spread of such viruses throughout tumors correlated well with improved antitumor efficacy and overall survival in two highly metastatic tumor models. Furthermore, nonreplicating viruses expressing relaxin did not increase metastases, suggesting that high level expression of relaxin will not enhance metastatic spread of tumors. In summary, the data show that relaxin may play a role in rearranging matrix components within tumors, which helps recombinant oncolytic adenoviruses to spread effectively throughout the tumor mass and thereby increase the extent of viral replication within the tumor. Expressing relaxin from Ad5/Ad35 fiber chimeric adenoviruses may prove a potent and novel approach to treating patients with cancer. [Cancer Res 2007;67(9):4399–406]
The Akt/Mammalian Target of Rapamycin Signal Transduction Pathway Is Activated in High-Risk Myelodysplastic Syndromes and Influences Cell Survival and Proliferation
Authors: Follo Matilde Y. , Mongiorgi Sara , Bosi Costanza , Cappellini Alessandra , Finelli Carlo , Chiarini Francesca , Papa Veronica , Libra Massimo , Martinelli Giovanni , Cocco Lucio , Martelli Alberto M. 
Published: May 2007

Abstract
The Akt/mammalian target of rapamycin (mTOR) signaling pathway is important for both cell growth and survival. In particular, an impaired regulation of the Akt/mTOR axis has been strongly implicated in mechanisms related to neoplastic transformation, through enhancement of cell proliferation and survival. Myelodysplastic syndromes (MDS) are a group of heterogeneous hematopoietic stem cell disorders characterized by ineffective hematopoiesis and by a high risk of evolution into acute myelogenous leukemia (AML). The pathogenesis of the MDS evolution into AML is still unclear, although some recent studies indicate that aberrant activation of survival signaling pathways could be involved. In this investigation, done by means of immunofluorescent staining, we report an activation of the Akt/mTOR pathway in high-risk MDS patients. Interestingly, not only mTOR was activated but also its downstream targets, 4E-binding protein 1 and p70 ribosomal S6 kinase. Treatment with the selective mTOR inhibitor, rapamycin, significantly increased apoptotic cell death of CD33+ (but not CD33−) cells from high-risk MDS patients. Rapamycin was ineffective in cells from healthy donors or low-risk MDS. Moreover, incubation of high-risk MDS patient CD34+ cells with rapamycin decreased the in vitro clonogenic capability of these cells. In contrast, the phosphoinositide 3-kinase inhibitor, LY294002, did not significantly affect the clonogenic activity of high-risk MDS cells. Taken together, our results indicate that the Akt/mTOR pathway is critical for cell survival and proliferation in high-risk MDS patients. Therefore, this signaling network could become an interesting therapeutic target for treating more advanced MDS cases. [Cancer Res 2007;67(9):4287–94]
Thermal Cycling Enhances the Accumulation of a Temperature-Sensitive Biopolymer in Solid Tumors
Authors: Dreher Matthew R. , Liu Wenge , Michelich Charles R. , Dewhirst Mark W. , Chilkoti Ashutosh 
Published: May 2007

Abstract
The delivery of anticancer therapeutics to solid tumors remains a critical problem in the treatment of cancer. This study reports a new methodology to target a temperature-responsive macromolecular drug carrier, an elastin-like polypeptide (ELP) to solid tumors. Using a dorsal skin fold window chamber model and intravital laser scanning confocal microscopy, we show that the ELP forms micron-sized aggregates that adhere to the tumor vasculature only when tumors are heated to 41.5°C. Upon return to normothermia, the vascular particles dissolve into the plasma, increasing the vascular concentration, which drives more ELPs across the tumor blood vessel and significantly increases its extravascular accumulation. These observations suggested that thermal cycling of tumors would increase the exposure of tumor cells to ELP drug carriers. We investigated this hypothesis in this study by thermally cycling an implanted tumor in nude mice from body temperature to 41.5°C thrice within 1.5 h, and showed the repeated formation of adherent microparticles of ELP in the heated tumor vasculature in each thermal cycle. These results suggest that thermal cycling of tumors can be repeated multiple times to further increase the accumulation of a thermally responsive polymeric drug carrier in solid tumors over a single heat-cool cycle. More broadly, this study shows a new approach—tumor thermal cycling—to exploit stimuli-responsive polymers in vivo to target the tumor vasculature or extravascular compartment with high specificity. [Cancer Res 2007;67(9):4418–24]
Phosphoinositide-3-Kinase Signaling Controls S-Phase Kinase–Associated Protein 2 Transcription via E2F1 in Pancreatic Ductal Adenocarcinoma Cells
Authors: Reichert Maximilian , Saur Dieter , Hamacher Rainer , Schmid Roland M. , Schneider Günter 
Published: May 2007

Abstract
The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G1 phase progression of PDAC cells. Gene profiling revealed several important regulators of G1-S phase progression controlled by PI3K signaling like p21Cip1, S-phase kinase–associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC. [Cancer Res 2007;67(9):4149–56]