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Tumour Formation (tumour + formation)
Selected AbstractsEcology-based screen identifies new metabolites from a Cordyceps -colonizing fungus as cancer cell proliferation inhibitors and apoptosis inducersCELL PROLIFERATION, Issue 6 2009Y. Chen Objectives:, This study aims to identify new anti-cancer agents from Cordyceps -colonizing fungi, using an ecology-based approach. It also aims to explore their anti-cell proliferative mechanisms, and to evaluate their anti-tumour effects in vivo. Materials and methods:, Extracts from Cordyceps -colonizing fungi were tested on HeLa cells, and active extracts were separated to obtain anti-tumour metabolites; their structures were elucidated by mass and nuclear magnetic resonance spectroscopy. Cell cycle analysis was evaluated using flow cytometry. Tumour formation assays were performed using C57BL/6J mice. Results:, Based on ecological considerations, the selected extracts were subjected to initial anti-tumour screening. Bioassay-guided fractionation of the active extract afforded two new epipolythiodioxopiperazines, named gliocladicillins A (1) and B (2). (A) 1 and B (2) inhibited growth of HeLa, HepG2 and MCF-7 tumour cells. Further study demonstrated that both preparations arrested the cell cycle at G2/M phase in a dose-dependent manner, and induced apoptosis through up-regulation of expression of p53, p21, and cyclin B, and activation of caspases-8, -9 and -3. These data imply that gliocladicillins A (1) and B (2) induce tumour cell apoptosis through both extrinsic and intrinsic pathways. In addition, in vivo studies showed that they displayed significant inhibitory effects on cell population growth of melanoma B16 cells imlanted into immunodeficient mice. Conclusions:, Gliocladicillins A (1) and B (2) are effective anti-tumour agents in vitro and in vivo and should be further evaluated for their potential in clinical use. [source] KEYNOTE ADDRESS Ku80-deletion causes early ageing and suppresses cancerJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 2 2009P. Hasty Ageing is widespread cellular decline resulting in a loss of fitness that is both pleiotropic and stochastic and influenced by both genetics and environment. As a result the fundamental underling causes of ageing are diverse and controversial. One potential ageing target is nuclear DNA, as it is a permanent blueprint that controls cellular processes. Thus, DNA replication and genome maintenance are highly regulated events that ensure faithful reproduction and maintenance of the blueprint and these pathways assure sufficient longevity for reproduction and survival of the species. As a consequence, imperfections or defects in maintaining the genome may contribute to ageing. Therefore, genome maintenance pathways are longevity-assurance mechanisms that sustain an organism long enough to reproduce and propagate. Chief among these mechanisms are those that respond to damaged DNA. There are two basics responses to genomic damage: DNA repair and cell cycle checkpoints. Both are considered to be tumour suppressors and are categorized as either caretakers or gatekeepers, respectively. Interestingly, observations of human and mouse pre-mature ageing models suggest these anti-tumour pathways impact the ageing process. Caretakers suppress cancer by repairing DNA damage caused by defects in replication or by a variety of agents including endogenously produced reactive by-products of oxygen metabolism and exogenous agents naturally encountered in our environment. As a consequence DNA is subject to a variety of insults that cause a diverse range of lesions and phenotypic outcomes. There are many forms of DNA damage including base lesions and double-strand breaks (DSBs) with the latter being more toxic. Cancer-causing chromosomal rearrangements may result if DSBs are not repaired properly. Additionally, an accumulation of these rearrangements may contribute to ageing since they increase in some cell types as humans and mice age. Furthermore, early ageing models suggest that defects in repairing DSBs lead to early ageing in humans and mice. Non-homologous end joining (NHEJ) is an important pathway for repairing DNA DSBs and is considered a caretaker. The Ku heterodimer (composed of Ku70 and Ku80) binds to DNA ends to initiate NHEJ, and defects in either Ku70 or Ku80 lead to increased levels of DNA DSBs and chromosomal rearrangements, leading many to believe Ku is a caretaker. Ku-mutant mice display increased GCRs, but without increased cancer. Instead, these mice show early ageing and shortened life span. Thus, Ku's role as a caretaker is uncertain as the low cancer levels may be due to Ku80-deletion or, instead, the low cancer levels may simply be a consequence of the shortened life span that prohibits sufficient time for tumours to develop. Gatekeepers respond to DNA damage by halting the cell cycle long enough for the DNA to be repaired. If the damage is irreparable, gatekeepers induce either apoptosis or senescence. These responses are deleterious to the cell but protect the organism from cancer as one potential outcome of genetic mutations is uncontrolled proliferation. p53 is critical for checkpoints and is the best-known gatekeeper because it is mutated in over half of all cancers. In addition, p53 activity influences many aspects of the Ku-mutant phenotype suggesting that Ku-deletion leads to persistent p53-mediated responses and presenting the possibility that low cancer levels and early ageing are caused by elevated gatekeeper responses. Our hypothesis is that Ku-mutant mice exhibit low cancer levels and, perhaps, ageing due to persistent p53-mediated responses to inefficiently repaired DNA. To test this hypothesis, Ku80-mutant mice were crossed to cancer-prone mice with either non-functional or functional gatekeeper responses. Ku80-mutant mice were crossed to p53-mutant mice to determine if Ku80-deletion exacerbates oncogenesis when gatekeeper responses are diminished. Ku80-mutant mice deleted for p53 exhibit early onset and high levels of two forms of cancer: pro-B cell lymphoma and medulloblastoma, thus supporting the hypothesis. Ku80-mutant mice were also crossed to APCMIN mice to determine if Ku80-deletion ameliorates oncogenesis gatekeeper responses are intact. APCMIN mice exhibit high levels of intestinal adenomas and adenocarcinomas but have normal p53-mediated responses to DNA damage. APCMIN mice, deleted for Ku80, exhibit about 67% fewer tumours than APCMIN mice with Ku80. Thus, deletion of Ku80 suppresses tumour formation, again supporting the hypothesis. Ku80-mutant cells and tissues were tested for p53-mediated DNA damage responses, levels of DNA damage, and mutations. Ku80-mutant fibroblasts exhibit elevated levels of p53-mediated DNA damage responses that increase p21-mediated cellular senescence. In addition, there are elevated levels DNA damage as seen by increased 53BP1 foci and elevated levels of chromosomal rearrangements. Thus, these data support the hypothesis that Ku80-deletion reduces tumors by elevating DNA damage gatekeeper responses to inefficiently repaired DNA. These data also support the possibility that the Ku80-mutant ageing phenotype is also due to elevated gatekeeper responses. [source] Cell transformation induced by hepatitis C virus NS3 serine proteaseJOURNAL OF VIRAL HEPATITIS, Issue 2 2001R. Zemel Persistent infection with hepatitis C virus (HCV) may lead to hepatocellular carcinoma (HCC). It has been suggested that HCV-encoded proteins are directly involved in the tumorigenic process. The HCV nonstructural protein NS3 has been identified as a virus-encoded serine protease. To study whether HCV NS3 has oncogenic activity, nontumorigenic rat fibroblast (RF) cells were stably transfected with an expression vector containing cDNA for the NS3 serine protease (nucleotides 3356,4080). The NS3 serine protease activity was determined in the transfected cells. The transfected cells grew rapidly and proliferated serum independently, lost contact inhibition, grew anchorage independently in soft agar and induced significant tumour formation in nude mice. Cells transfected with an expression vector containing a mutated NS3 serine protease (serine 139 to alanine at the catalytic site) showed no transforming abilities; their growth was dependent on serum and they did not grow anchorage independently in soft agar. Moreover, cells transfected with the NS3 serine protease and treated with the chymotrypsin inhibitors TPCK and PMSF (a serine protease inhibitor) lost their transforming feature. These results suggest that the NS3 serine protease of HCV is involved in cell transformation and that the ability to transform requires an active enzyme. [source] Derivation, safety and efficacy of a Marek's disease vaccine developed from an Australian isolate of very virulent Marek's disease virusAUSTRALIAN VETERINARY JOURNAL, Issue 1 2002RC KARPATHY Objective To develop a serotype 1 Marek's disease (MD) vaccine from a very virulent MDV (vvMDV) pathotype and demonstrate safety and efficacy against early challenge with very virulent field strains in the presence of maternal antibody. Study design Strain BH 16 was isolated and attenuated by serial cell culture passage. One of two cloned passages was selected for vaccine development following early laboratory-scale protection trials in commercial birds. Comparative protection trials were carried out on the BH 16 vaccine and on a CVI 988 Rispens vaccine using commercial and SPF chickens. Challenge viruses used were either a low passage strain BH 16 virus, the Woodlands No. 1 strain or MPF 57 strain of MDV. The BH 16 vaccine was back-passaged in SPF chickens six times and virus recovered from the final passage and the original vaccine virus were tested for safety. The immunosuppressive potential of the BH 16 and Rispens vaccines was also assessed in parallel. Results The BH 16 and Rispens vaccines induced comparable levels of protection when used as monovalent or multi-valent vaccines, although protection achieved with the mono-valent vaccines was lower. No gross tumour formation was evident in any birds receiving the BH 16 vaccine or bird-passaged virus, although microscopic lesions were present in 2/12 birds that received the bird-passaged virus. In tests for immunosuppression, there was no histological evidence of damage to either the bursa of Fabricius or the thymus. Conclusion The BH 16 vaccine was shown to be safe and at least as protective as the Rispens vaccine against three highly virulent MD challenge viruses. [source] Evolutionary plasticity and cancer breakpoints in human chromosome 3BIOESSAYS, Issue 11-12 2008Aurora Ruiz-Herrera In this review, we focus on the evolutionary and biomedical aspects of the architecture of human chromosome 3 (HSA3) by analyzing chromosomal regions that have been conserved during the evolutionary process, compared to those that have been involved in the genomic restructuring of different placental lineages. Given that the organization of human chromosome 3 is derived when compared to the ancestral primate karyotype, and is an autosome that is commonly implicated in human tumour formation, we examined the patterns of change and the genomic consequences that have resulted from its complex evolutionary history. The data show four discrete chromosomal regions that are frequently implicated in chromosomal rearrangements (3p25, 3p22, 3p12 and 3q21). These are rich in repetitive elements and are commonly implicated in structural rearrangements that underpin human genomic disorders and neoplasias. Additional Supporting Information may be found in the online version of this article. BioEssays 30:1126,1137, 2008. © 2008 Wiley Periodicals, Inc. [source] Patterns of spread in an orthotopic mouse model of bladder cancerBJU INTERNATIONAL, Issue 2006J.P. BRENNAN Purpose:, To develop an orthotopic model of muscle-invasive transitional cell carcinoma (TCC) of the bladder which models primary tumour growth and metastasis. Methodology:, Cell lines were derived from the TCC cell line T24 (Tsu-Pr1) using in vivo selection for metastatic ability (Chaffer et al. Clin Exp Metastasis 2005; 22(2): 115,25). Each of these cell lines (Tsu-Pr1 and sub-lines, B1 and B2) was then injected intramurally into the mouse bladder wall (n = 25 × 3). The cell lines were also injected intravesically and intraperitoneally (n = 15 × 3 in each group). Results:, There were no differences between the three sub-lines in primary tumour formation, presence of macroscopic metastases and survival. This model produced more macroscopic and lymph node metastases in comparison with other orthotopic models reported in the literature. After intraperitoneal injection, the B2 cell line produced a higher number of discrete intra-abdominal masses in comparison with the parental line. This is likely to be related to the phenotype of the cells with parental cells being more mesenchymal, versus the B2 sub-line, which has more epithelial characteristics. Conclusion:, The TSU-Pr1 series is a useful, clinically relevant model of muscle-invasive TCC. In addition, this model may also provide insights into the role of mesenchymal-epithelial transition in the metastatic process. [source] Genes differentially expressed in prostate cancerBJU INTERNATIONAL, Issue 8 2004I.E. Eder Because of the heterogeneity of prostate cancer knowledge about the genes involved in prostate carcinogenesis is still very limited. Previously, the use of novel high-throughput technologies offered the possibility to investigate broad gene expression profiles and thus helped to improve understanding of the molecular basis of prostate disease. Many candidate genes have been identified so far which have a more or less strong effect on prostate cancer. This vast number of gene expression changes show that it is unlikely that only one gene promotes prostate cancer. Conversely, it seems more likely that a broad network of molecular changes is involved in the complex cascade of events which lead to tumour formation and progression, respectively. A few of these novel molecular targets are currently under clinical evaluation. This paper gives an overview of several interesting candidate genes which may be useful as improved biomarkers for diagnosis or as targets for developing novel treatment methods. [source] Evidence that dysregulated DNA mismatch repair characterizes human nonmelanoma skin cancerBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2008L.C. Young Summary Background, In addition to an established role in the repair of postreplicative DNA errors, DNA mismatch repair (MMR) proteins also contribute to cellular responses to exogenous DNA damage. Previously, we have shown that Msh2 -null mice display increased sensitivity to ultraviolet (UV) B-induced tumorigenesis, but squamous cell carcinomas (SCC) generated are microsatellite stable, suggesting a role for MMR other than postreplicative repair in UV-induced cutaneous tumour formation. Objectives, We questioned whether there was evidence of MMR dysfunction in human SCC, thus validating the mouse models of MMR-dependent UVB-induced skin cancer. Methods, Using tissue microarrays we examined both nuclear and cytoplasmic levels of MMR proteins MSH2, MSH6, MSH3, MLH1 and PMS2 in more than 200 cases of cutaneous SCC and basal cell carcinoma (BCC). Results, We found that subsets of these 10 MMR protein measures were increased in nonmelanoma skin cancer (NMSC) compared with normal epidermal samples; this was particularly true of SCC. In fact, based on post hoc tests and MMR protein distribution patterns, BCC was distinct from SCC. With the exception of nuclear MSH2, the BCC had lower levels of identified MMR protein measures than SCC. We believe this to be important because not only is SCC more aggressive than BCC, but evidence suggests that these two NMSC subtypes arise through different molecular pathways. Conclusions, In combination with previously established roles for MMR proteins in response to UVB-induced DNA damage, our data point towards an expanded perspective of the importance of MMR proteins in the suppression of UVB-induced tumorigenesis and, potentially, tumour behaviour. [source] Subretinal pigment dispersion following transpupillary thermotherapy for choroidal melanomaACTA OPHTHALMOLOGICA, Issue 4 2002Hayyam Kiratli ABSTRACT. Purpose:, To report the case of a patient who developed considerable subretinal pigment/debris dispersion following transpupillary thermotherapy (TTT). This type of tumour response is extremely rare with this relatively new therapeutic modality. Methods:, A 50-year-old man with a left juxtapapillary choroidal melanoma measuring 8 × 6 × 4.3 mm was treated with 810 nm diode laser TTT administered in two sessions. Spot size was 3 mm and the power setting was 450 mW. Results:, Four months after the first treatment session, a considerable amount of pigment/debris was seen to have dispersed in the subretinal space, accumulating mainly in the macular area. Over a 12-month follow-up, the tumour showed progressive shrinkage without any change in the amount or location of the shed pigment/debris. No new tumour formation, recurrence or systemic metastases were detected. Conclusion:, Subretinal pigment/debris dispersion is an unusual complication after TTT and requires close follow-up. There has been no short-term compromise on the life or visual acuity of this patient. [source] | |||||||||||||