bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matrix Metalloproteinase Activity Modulates Tumor Size, Cell Motility, and Cell Invasiveness in Murine Aggressive Fibromatosis
Authors: Kong Yuan , Poon Raymond , Nadesan Puviindran , Di Muccio Tamara , Fodde Riccardo , Khokha Rama , Alman Benjamin A. 
Published: September 2005

AbstractMatrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) regulate the degradation of extracellular matrix components and play important roles in the progression of select neoplastic processes. The locally invasive soft tissue tumor, aggressive fibromatosis (also called desmoid tumor), is caused by mutations resulting in β-catenin-mediated T-cell factor (tcf)-dependent transcriptional activity. Because β-catenin can regulate MMP expression, we investigated the expression of several MMPs and TIMPs in aggressive fibromatosis tumors that develop in Apc+/Apc1638N mice. Mmp-3 and Timp-1 were differentially regulated (5-fold and 0.5-fold, respectively) in tumors compared with normal fibrous tissue. Conditioned media from tumor cells showed an increased ability to degrade collagen, and inhibition of MMPs using GM6001 decreased the ability of the tumor cells to invade through Matrigel. Both the treatment of Apc/Apc1638N mice with GM6001 or crossing with a transgenic mouse that overexpresses Timp-1 resulted in a significant reduction in tumor volume. Surprisingly, overexpression of Timp-1 also resulted in a 50% increase in tumor number. Although TIMP-1 can induce growth stimulatory effects in some cell types, we found no difference in proliferation or apoptosis rate in cells from tumors that developed in the Timp-1–transgenic mice compared with mice that did not express the Timp-1 transgene, suggesting that TIMP-1 promotes aggressive fibromatosis tumor formation through an alternate mechanism. These data suggest that MMPs play a crucial role in regulating the invasiveness of mesenchymal cells and in modulating aggressive fibromatosis tumor progression. Because this is a locally invasive tumor, MMP inhibition could slow tumor growth and may prove to be an effective adjuvant therapy.
Genome-Wide Identification of Genes Conferring Resistance to the Anticancer Agents Cisplatin, Oxaliplatin, and Mitomycin C
Authors: Wu H. Irene , Brown James A. , Dorie Mary J. , Lazzeroni Laura , Brown J. Martin 
Published: September 2005

Abstract
Cisplatin is a crucial agent in the treatment of many solid tumors, yet many tumors have either acquired or intrinsic resistance to the drug. We have used the homozygous diploid deletion pool of Saccharomyces cerevisiae, containing 4728 strains with individual deletion of all nonessential genes, to systematically identify genes that when deleted confer sensitivity to the anticancer agents cisplatin, oxaliplatin, and mitomycin C. We found that deletions of genes involved in nucleotide excision repair, recombinational repair, postreplication repair including translesional synthesis, and DNA interstrand cross-link repair resulted in sensitivity to all three of the agents, although with some differences between the platinum drugs and mitomycin C in the spectrum of required translesional polymerases. Putative defective repair of oxidative damage (imp2′Δ strain) also resulted in sensitivity to platinum and oxaliplatin, but not to mitomycin C. Surprisingly in light of their different profiles of clinical activity, cisplatin and oxaliplatin have very similar sensitivity profiles. Finally, we identified three novel genes (PSY1–3, “platinum sensitivity”) that, when deleted, demonstrate sensitivity to cisplatin and oxaliplatin, but not to mitomycin C. Our results emphasize the importance of multiple DNA repair pathways responsible for normal cellular resistance to all three of the agents. Also, the similarity of the sensitivity profiles of the platinum agents with that of the known DNA interstrand cross-linking agent mitomycin C, and the importance of the gene PSO2 known to be involved in DNA interstrand cross-link repair strongly suggests that interstrand cross-links are important toxic lesions for cisplatin and oxaliplatin, at least in yeast.
Facilitating Role of Preprotachykinin-I Gene in the Integration of Breast Cancer Cells within the Stromal Compartment of the Bone Marrow
Authors: Rao Gayatri , Patel Prem S. , Idler Suji P. , Maloof Paul , Gascon Pedro , Potian Julius A. , Rameshwar Pranela 
Published: September 2005

Abstract
Despite early detection of breast cancer, patients’ survival may be compromised if the breast cancer cells (BCCs) enter the bone marrow (BM). It is highly probable that BCCs enter the BM long before clinical detection. An in vitro coculture model with BM stroma and BCCs (cell lines; primary cells from stage III BC, n = 7, and stage M0, n = 3) mimicked early entry of BCCs into the BM. In coculture, BCCs exhibit contact inhibition and do not require otherwise needed growth supplements. Stromal growth rate was increased 2-fold in coculture. The inclusion of BCCs in stromal support of long-term culture-initiating cell assay frequencies show no difference (38 ± 3 versus 36 ± 6). Nontumorigenic breast cells (patients and cell lines) did not survive in coculture, suggesting that the model could select for malignant population in surgical breast tissues. Cocultures were able to select cells with 73 ± 7% cloning efficiencies and with the ability to form cocultures with BM stroma. Preprotachykinin-I (PPT-I), a gene that is conserved by evolution, facilitates BCC integration as part of the stromal compartment. This was deduced as follows: (a) nontumorigenic breast cells (n = 4) genetically engineered to express PPT-I and led to anchorage-independent growth, foci formation, and formation of cocultures; and (b) suppression of PPT-I in BCCs (n = 5) with pPMSKH1-PPT-I small interfering RNA reverted the cells to nontumorigenic phenotypes and was undetectable in the BM nude mice. The evidence supports that the PPT-I gene facilitates the integration of BCCs in the stromal compartment during a period before clinical detection, without disrupting hematopoietic activity.
Lipoptosis
Authors: Pohle Tina , Brändlein Stephanie , Ruoff Nele , Müller-Hermelink Hans Konrad , Vollmers H. Peter 
Published: September 2005

Abstract
A balanced lipid metabolism is crucial for all cells. Disturbance of this homeostasis by nonphysiological intracellular accumulation of fatty acids can result in apoptosis. This was proven in animal studies and was correlated to some human diseases, like lipotoxic cardiomyopathy. Some metabolic mechanisms of lipo-apoptosis were described, and some causes were discussed, but reagents, which directly induce lipo-apoptosis, have thus far not been identified. The human monoclonal IgM antibody SAM-6 was isolated from a stomach cancer patient by using the conventional human hybridoma technology (trioma technique). The addition of SAM-6 to tumor cells leads to an increase in the intracellular accumulation of neutral lipids, followed by tumor cell apoptosis. The antibody SAM-6 does not react with noncancerous human epithelial and fibroblastic cells, because the Mr 140,000 membrane molecule, recognized by the antibody, is specifically expressed on human malignant cells. The antibody is coded by the germ-line genes IgHV3-30.3*01 and IgLV3-1*01 and is a component of the innate immunity to cancer. In this article, we describe an antibody-induced tumor-specific cell death, named lipoptosis. This is, to our knowledge, the first description of this specific form of lipo-apoptosis as an antibody-mediated mechanism of tumor cell killing.
Detection of an Involvement of the Human Mismatch Repair Genes
hMLH1
and
hMSH2
in Nucleotide Excision Repair Is Dependent on UVC Fluence to Cells
Authors: Lee David F. , Drouin Regen , Pitsikas Photini , Rainbow Andrew J. 
Published: September 2005

Abstract
There is conflicting evidence for the role of the mismatch repair (MMR) genes hMLH1 and hMSH2 in the transcription-coupled repair (TCR) pathway of nucleotide excision repair. In the present work, we have examined the role of these MMR genes in nucleotide excision repair using two reporter gene assays. AdHCMVlacZ is a replication-deficient recombinant adenovirus that expresses the β-galactosidase reporter gene under the control of the human cytomegalovirus immediate early promoter. We have reported previously a reduced host cell reactivation (HCR) for β-galactosidase expression of UVC-irradiated AdHCMVlacZ in TCR-deficient Cockayne syndrome (CS) fibroblasts compared with normal fibroblasts, indicating that HCR depends, at least in part, on TCR. In addition, we have reported that UVC-enhanced expression of the undamaged reporter gene is induced at lower UVC fluences to cells and at higher levels after low UVC fluences in TCR-deficient compared with normal human fibroblasts, suggesting that persistent damage in active genes triggers increased activity from the human cytomegalovirus-driven reporter construct. We have examined HCR and UV-enhanced expression of the reporter gene in hMLH1-deficient HCT116 human colon adenocarcinoma cells and HCT116-chr3 cells (the MMR-proficient counterpart of HCT116) as well as hMSH2-deficient LoVo human colon adenocarcinoma cells and their hMSH2-proficient counterpart SW480 cells. We show a greater UV-enhanced expression of the undamaged reporter gene after low UVC exposure in HCT116 compared with HCT116-chr3 cells and in LoVo compared with SW480 cells. We show also a reduced HCR in HCT116 compared with HCT116-chr3 cells and in LoVo compared with SW480 cells. However, the reduction in HCR was less or absent when cells were pretreated with UVC. These results suggest that detection of an involvement of hMLH1 and hMSH2 in TCR is dependent on UVC (254 nm) fluence to cells.
ATM and DNA-PK Function Redundantly to Phosphorylate H2AX after Exposure to Ionizing Radiation
Authors: Stiff Tom , O’Driscoll Mark , Rief Nicole , Iwabuchi Kuniyoshi , Löbrich Markus , Jeggo Penny A. 
Published: September 2005

Abstract
H2AX phosphorylation is an early step in the response to DNA damage. It is widely accepted that ATM (ataxia telangiectasia mutated protein) phosphorylates H2AX in response to DNA double-strand breaks (DSBs). Whether DNA-dependent protein kinase (DNA-PK) plays any role in this response is unclear. Here, we show that H2AX phosphorylation after exposure to ionizing radiation (IR) occurs to similar extents in human fibroblasts and in mouse embryo fibroblasts lacking either DNA-PK or ATM but is ablated in ATM-deficient cells treated with LY294002, a drug that specifically inhibits DNA-PK. Additionally, we show that inactivation of both DNA-PK and ATM is required to ablate IR-induced H2AX phosphorylation in chicken cells. We confirm that H2AX phosphorylation induced by DSBs in nonreplicating cells is ATR (ataxia telangiectasia and Rad3-related protein) independent. Taken together, we conclude that under most normal growth conditions, IR-induced H2AX phosphorylation can be carried out by ATM and DNA-PK in a redundant, overlapping manner. In contrast, DNA-PK cannot phosphorylate other proteins involved in the checkpoint response, including chromatin-associated Rad17. However, by phosphorylating H2AX, DNA-PK can contribute to the presence of the damage response proteins MDC1 and 53BP1 at the site of the DSB.
Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes
Authors: Pett Mark R. , Alazawi William O. F. , Roberts Ian , Dowen Sally , Smith David I. , Stanley Margaret A. , Coleman Nicholas 
Published: September 2005

Abstract
Whereas two key steps in cervical carcinogenesis are integration of high-risk human papillomavirus (HR-HPV) and acquisition of an unstable host genome, the temporal association between these events is poorly understood. Chromosomal instability is induced when HR-HPV E7 oncoprotein is overexpressed from heterologous promoters in vitro. However, it is not known whether such events occur at the “physiologically” elevated levels of E7 produced by deregulation of the homologous HR-HPV promoter after integration. Indeed, an alternative possibility is that integration in vivo is favored in an already unstable host genome. We have addressed these issues using the unique human papillomavirus (HPV) 16-containing cervical keratinocyte cell line W12, which was derived from a low-grade squamous intraepithelial lesion and thus acquired HPV16 by “natural” infection. Whereas W12 at low passage contains HPV16 episomes only, long-term culture results in the emergence of cells containing integrated HPV16 only. We show that integration of HPV16 in W12 is associated with 3′ deletion of the E2 transcriptional repressor, resulting in deregulation of the homologous promoter of the integrant and an increase in E7 protein levels. We further demonstrate that high-level chromosomal instability develops in W12 only after integration and that the forms of instability observed correlate with the physical state of HPV16 DNA and the level of E7 protein. Whereas intermediate E7 levels are associated with numerical chromosomal abnormalities, maximal levels are associated with both numerical and structural aberrations. HR-HPV integration is likely to be a critical event in cervical carcinogenesis, preceding the development of chromosomal abnormalities that drive malignant progression.
Bcl-2-Dependent Modulation of Swelling-Activated Cl− Current and ClC-3 Expression in Human Prostate Cancer Epithelial Cells
Authors: Lemonnier Loïc , Shuba Yaroslav , Crepin Alexandre , Roudbaraki Morad , Slomianny Christian , Mauroy Brigitte , Nilius Bernd , Prevarskaya Natalia , Skryma Roman 
Published: September 2005

AbstractCell shrinkage is an integral part of apoptosis. However, intimate mechanisms linking apoptotic events to the alterations in cell volume homeostasis remain poorly elucidated. We investigated how overexpression of Bcl-2 oncoprotein, a key antiapoptotic regulator, in lymph node carcinoma of the prostate (LNCaP) prostate cancer epithelial cells interferes with the volume-regulated anion channel (VRAC), a major determinant of regulatory volume decrease. Bcl-2 overexpression resulted in the doubling of VRAC-carried swelling-activated Cl− current (ICl,swell) and weakened ICl,swell inhibition by store-operated Ca2+ channel (SOC)-transported Ca2+. This also was accompanied by substantial up-regulation of ClC-3 protein, a putative molecular candidate for the role of VRAC. ClC-3-specific antibody suppressed ICl,swell in the wild-type and Bcl-2-overexpressing LNCaP cells. Epidermal growth factor treatment of wild-type LNCaP cells, promoting their proliferation, resulted in the enhancement of endogenous Bcl-2 expression and associated increases in ClC-3 levels and ICl,swell magnitude. We conclude that Bcl-2-induced up-regulation of ICl,swell, caused by enhanced expression of ClC-3 and weaker negative control from SOC-transported Ca2+, would strengthen the ability of the cells to handle proliferative volume increases and thereby promote their survival and diminish their proapoptotic potential.
CD4+ T-Cell Recognition of Mutated B-RAF in Melanoma Patients Harboring the V599E Mutation
Authors: Sharkey Melinda S. , Lizée Gregory , Gonzales Monica I. , Patel Sima , Topalian Suzanne L. 
Published: September 2005

AbstractThe potential of antigen-directed cancer immunotherapy has not been fully realized, perhaps because many commonly targeted tumor associated proteins are not essential to maintaining the malignant cell phenotype. A constitutively activating mutation in the signaling molecule BRAF is expressed frequently in melanomas and may play an important role in the biology of this disease. A 29-mer B-Raf peptide incorporating the V599E mutation was used for in vitro stimulation of lymphocytes derived from melanoma patients, generating MHC class II-restricted CD4+ T cells specific for this peptide as well as for melanoma cells expressing B-Raf V599E. Mutated B-Raf exemplifies targets that may be ideal for immunotherapy.
Tobacco Carcinogen-Induced Cellular Transformation Increases Activation of the Phosphatidylinositol 3′-Kinase/Akt Pathwayin Vitroandin Vivo
Authors: West Kip A. , Linnoila Ilona R. , Belinsky Steven A. , Harris Curtis C. , Dennis Phillip A. 
Published: September 2005

AbstractThe role of the phosphatidylinositol 3′-kinase (PI3K)/Akt pathway during tobacco carcinogen-induced transformation is unknown. To address this question, we evaluated this pathway in isogenic immortalized or tumorigenic human bronchial epithelial cells in vitro, as well as in progressive murine lung lesions induced by a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Compared with immortalized cells, tumorigenic cells had greater activation of the PI3K/Akt pathway, enhanced survival, and increased apoptosis in response to inhibition of the pathway. In vivo, increased activation of Akt and mammalian target of rapamycin was observed with increased phenotypic progression. Collectively, these results support the hypothesis that maintenance of Akt activity is necessary for survival of preneoplastic as well as transformed lung epithelial cells and suggest that inhibition of the PI3K/Akt pathway might be a useful approach to arrest lung tumorigenesis.
Early Occurrence of
RASSF1A
Hypermethylation and Its Mutual Exclusion with
BRAF
Mutation in Thyroid Tumorigenesis
Authors: Xing Mingzhao , Cohen Yoram , Mambo Elizabeth , Tallini Giovanni , Udelsman Robert , Ladenson Paul W. , Sidransky David 
Published: September 2005

Abstract
Follicular epithelial cell-derived thyroid tumors are common neoplasms comprised mainly of benign thyroid adenomas, follicular thyroid cancers, and papillary thyroid cancers (PTCs). Hypermethylation of the tumor suppressor gene RASSF1A and activating mutation of BRAF gene have been reported recently in thyroid cancers. To additionally investigate the roles of these two epigenetic/genetic alterations in thyroid tumor progression, we examined their occurrences and relationship in both benign and malignant thyroid neoplasms. With real-time quantitative methylation-specific PCR, we found that 4 of 9 (44%) benign adenomas, 9 of 12 (75%) follicular thyroid cancers tumors, and 6 of 30 (20%) of PTC tumors harbored promoter methylation in ≥25% of RASSF1A alleles. Additional quantitative analysis revealed RASSF1A methylation only in BRAF mutation-negative PTCs. A similar inverse correlation of RASSF1A methylation with BRAF mutation was seen in thyroid tumor cell lines. Our results, therefore, suggest that epigenetic inactivation of RASSF1A through aberrant methylation is an early step in thyroid tumorigenesis. Like the previously reported mutually exclusive relationship between BRAF mutation and other Ras pathway components such as RET/PTC rearrangement, a mutually exclusive relationship also exists between BRAF mutation and RASSF1A methylation in thyroid tumorigenesis.
Local Administration of Granulocyte/Macrophage Colony-stimulating Factor Increases the Number and Activation State of Dendritic Cells in the Sentinel Lymph Node of Early-Stage Melanoma
Authors: Vuylsteke Ronald J. C. L. M. , Molenkamp Barbara G. , Gietema Hester A. , van Leeuwen Paul A. M. , Wijnands Pepijn G. J. T. B. , Vos Wim , van Diest Paul J. , Scheper Rik J. , Meijer Sybren , de Gruijl Tanja D. 
Published: September 2005

Abstract
The initial tumor-draining lymph node, the sentinel lymph node, not only constitutes the first expected site of micrometastasis but also the first point of contact between tumor-associated antigens and the adaptive immune system. A tumor-induced decrease in the frequency and activation state of sentinel lymph node dendritic cells will impair the generation of effective antitumor T-cell responses and increase the likelihood of metastatic spread. Here, we demonstrate that intradermal administration of granulocyte macrophage-colony stimulating factor around the excision site of stage I primary melanoma tumors increases the number and activation state of dendritic cells in the paracortical areas of the sentinel lymph node and enhances their binding to T cells. We conclude that local treatment of melanoma patients with granulocyte macrophage-colony stimulating factor, before surgery, conditions the sentinel lymph node microenvironment to enhance mature dendritic cell recruitment and hypothesize that this may be more conducive to the generation of T-cell–mediated antitumor immunity.
PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells
Authors: Blank Christian , Brown Ian , Peterson Amy C. , Spiotto Mike , Iwai Yoshiko , Honjo Tasuku , Gajewski Thomas F. 
Published: September 2005

AbstractAlthough increased circulating tumor antigen-specific CD8+ T cells can be achieved by vaccination or adoptive transfer, tumor progression nonetheless often occurs through resistance to effector function. To develop a model for identifying mechanisms of resistance to antigen-specific CTLs, poorly immunogenic B16-F10 melanoma was transduced to express the Kb-binding peptide SIYRYYGL as a green fluorescent protein fusion protein that should be recognized by high-affinity 2C TCR transgenic T cells. Although B16.SIY cells expressed high levels of antigen and were induced to express Kb in response to IFN-γ, they were poorly recognized by primed 2C/RAG2−/− T cells. A screen for candidate inhibitory ligands revealed elevated PD-L1/B7H-1 on IFN-γ-treated B16-F10 cells and also on eight additional mouse tumors and seven human melanoma cell lines. Primed 2C/RAG2−/−/PD-1−/− T cells showed augmented cytokine production, proliferation, and cytolytic activity against tumor cells compared with wild-type 2C cells. This effect was reproduced with anti-PD-L1 antibody present during the effector phase but not during the priming culture. Adoptive transfer of 2C/RAG2−/−/PD-1−/− T cells in vivo caused tumor rejection under conditions in which wild-type 2C cells or CTLA-4-deficient 2C cells did not reject. Our results support interfering with PD-L1/PD-1 interactions to augment the effector function of tumor antigen-specific CD8+ T cells in the tumor microenvironment.