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Cancer Formation (cancer + formation)
Selected AbstractsPERSPECTIVE: EMBEDDED MOLECULAR SWITCHES, ANTICANCER SELECTION, AND EFFECTS ON ONTOGENETIC RATES: A HYPOTHESIS OF DEVELOPMENTAL CONSTRAINT ON MORPHOGENESIS AND EVOLUTIONEVOLUTION, Issue 5 2003Kathryn D. Kavanagh Abstract The switch between the cell cycle and the progress of differentiation in developmental pathways is prevalent throughout the eukaryotes in all major cell lineages. Disruptions to the molecular signals regulating the switch between proliferative and differentiating states are severe, often resulting in cancer formation (uncontrolled proliferation) or major developmental disorders. Uncontrolled proliferation and developmental disorders are potentially lethal defects in the developing animal. Therefore, natural selection would likely favor a tightly controlled regulatory mechanism to help prevent these fundamental defects. Although selection is usually thought of as a consequence of environmental or ecological influences, in this case the selective force to maintain this molecular switch is internal, manifested as a potentially lethal developmental defect. The morphogenetic consequences of this prevalent, deeply embedded, and tightly controlled mechanistic switch are currently unexplored, however experimental and correlative evidence from several sources suggest that there are important consequences on the control of growth rates and developmental rates in organs and in the whole animal. These observations lead one to consider the possibility of a developmental constraint on ontogenetic rates and morphological evolution maintained by natural selection against cancer and other embryonic lethal defects. [source] Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor , resistant cellsGENES, CHROMOSOMES AND CANCER, Issue 2 2008Swati Biswas The mutational inactivation of transforming growth factor , receptor type II (TGFBR2) occurs in ,30% of colon cancers and promotes the formation of colon cancer by inhibiting the tumor suppressor activity of the TGFB signaling pathway. TGFBR2 mutations occur in >90% of microsatellite unstable (MSI) colon cancers and affect a polyadenine tract in exon 3 of TGFBR2, called BAT-RII, which is vulnerable to mutation in the setting of DNA mismatch repair (MMR) system deficiency. In light of the vulnerable nature of the BAT-RII tract in the setting of MMR inactivation and the favorable effects of TGFBR2 inactivation in colon cancer, analysis of TGFBR2 inactivation provides an opportunity to assess the roles of genomic instability vs. clonal selection in cells acquiring TGFBR2 BAT-RII tract mutations in MSI colon cancer formation. The contribution of genomic instability and/or clonal evolution to the mutational inactivation of TGBFR2 in MSI colon cancers has not been studied in a systematic way that would allow a determination of the relative contribution of these two mechanisms in the formation of MSI colon cancer. It has not been demonstrated whether the BAT-RII tract mutations are strictly a consequence of the BAT-RII region being hypermutable in the setting of MMR deficiency or if the mutations are rather a consequence of clonal selection pressure against the TGFB receptor. Through the use of defined cell line systems, we show that both genomic instability and clonal selection of TGFB resistant cells contribute to the high frequency of TGFBR2 mutations in MSI colon cancer. © 2007 Wiley-Liss, Inc. [source] The contribution of hepatic steroid metabolism to serum estradiol and estriol concentrations in nonylphenol treated MMTVneu mice and its potential effects on breast cancer incidence and latencyJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2005Ricardo Acevedo Abstract The two major pathways for the metabolism of estradiol-17, (E2) are the 2- and 16-hydroxylase pathways. Research has suggested that the increased production of the estrogenically active 16-hydroxy products such as estriol (E3) may be involved in increased susceptibility to breast cancer. 4-Nonylphenol (4-NP) is an environmental estrogen that also can activate the pregnane-X receptor (PXR) and induce P-450 enzymes responsible for the production of E3. It is hypothesized that 4-NP may act in part as an environmental estrogen by increasing E3 production. Based on its affinity for the estrogen receptor (ER) alone, 4-NP may be more potent than predicted at increasing mammary cancer incidence in the MMTVneu mouse. Female mice were treated per os for 7 days at 0, 25, 50 or 75 mg kg,1 day,1 4-NP to investigate the effects of 4-NP on hepatic estrogen metabolism after an acute treatment. 4-Nonylphenol increased the hepatic formation of E3 in a dose-dependent manner. However, serum E3 concentrations were only increased at 25 mg kg,1 day,1 presumably due to direct inhibition of E3 formation by 4-NP. MMTVneu mice were then treated for 32 weeks at 0, 30 or 45 mg kg,1 day,1 4-NP to determine its effects on mammary cancer formation and estrogen metabolism. 4-Nonylphenol increased mammary cancer formation in the MMTVneu mice at 45 mg kg,1 day,1 but not at 30 mg kg,1 day,1. Mice treated with an equipotent dose of E2, 10 µg kg,1 day,1, based on the relative binding affinities of nonylphenol and estradiol for ER,, did not develop mammary cancer. This suggests that nonylphenol is more potent than predicted based on its affinity for the estrogen receptor. However, no changes in serum E3 concentrations or hepatic E3 production were measured after the chronic treatment. Changes in E3 formation were correlated with increased CYP2B levels after the 7 day 4-NP treatment, and repression of CYP2B and CYP3A after 32 weeks of 4-NP treatment. Microarray analysis and Q-PCR of liver mRNA from the mice treated for 32 weeks demonstrated a decrease in RXR,, the heterodimeric partner of the PXR, which may in part explain the repressed transcription of the P450s measured. In conclusion, 4-NP treatment for 32 weeks increased mammary cancer formation at a dose of 45 mg kg,1 day,1. However, chronic treatment with 4-NP did not increase hepatic E3 formation or serum E3 concentrations. The transient induction by 4-NP of hepatic E3 formation and serum concentrations is most likely not involved in the increased incidence of mammary cancer in MMTVneu mice since E3 serum concentrations were only increased at 25 mg kg,1 day,1, a dose that was not sufficient to induce mammary tumor formation. Nevertheless, the induced hepatic E3 production in the acute exposures to 4-NP was indicative of an increase in mammary cancer incidence after the chronic exposure. Copyright © 2005 John Wiley & Sons, Ltd. [source] Urokinase gene 3,-UTR T/C polymorphism is associated with oral cancerJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 5 2004Ming-Hsui Tsai Abstract Urokinase is thought to be involved in the formation of oral cancer, although there is a lack of genetic evidence. Our aim was to study single nucleotide polymorphisms in order to investigate the possibility. A total of 130 oral cancer patients and 105 controls were studied. Polymerase chain reaction (PCR) based restriction analysis was used to identify the C/T polymorphism of the urokinase gene, which is located on the 3,-untranslated region (3,-UTR) of chromosome 10. There was a significant difference in the distribution of the urokinase gene 3,-UTR C/T polymorphism frequency between cancer patients and the normal control group (P<0.05). The "T" allele was prominent in the cancer group. The odds ratio for the risk of the "T" allele in cancer patients was 2.71 (95% CI=1.325,5.562). The cancer patients were further categorized according to gender and whether or not they were habitual smokers or betel nut chewers. These clinical parameters were then compared with tumor cell differentiation and tumor progression. No significant differences were found. Therefore, the urokinase gene 3,-UTR "T" allele is associated with oral cancer and may play a role in oral cancer formation. However, we did not find the relationship between tumor progression and this polymorphism. J. Clin. Lab. Anal. 18:276,279, 2004. © 2004 Wiley-Liss, Inc. [source] Cloning and expression profile of FLT3 gene during progenitor cell-dependent liver regenerationJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2007Iraz T Aydin Abstract Background and Aim:, The liver has a unique capacity to regenerate upon exposure to viral infections, toxic reactions and cancer formation. Liver regeneration is a complex phenomenon in which several factors participate during its onset. Cellular proliferation is an important component of this process and the factors that regulate this proliferation have a vital role. FLT3, a well-known hematopoietic stem cell and hepatic lineage surface marker, is involved in proliferative events of hematopoietic stem cells. However, its contribution to liver regeneration is not known. Therefore, the aim of this study was to clone and examine the role of FLT3 during liver regeneration in rats. Methods:, Partial cDNA of rat homolog of FLT3 gene was cloned from thymus and the tissue specific expression of this gene at mRNA and protein levels was examined by RT-PCR and Western blot. After treating with 2-AAF and performing hepatectomy in rats to induce progenitor-dependent liver regeneration, the mRNA and protein expression profile of FLT3 was investigated by real-time PCR and Western blot during liver regeneration. In addition, cellular localization of FLT3 protein was determined by immunohistochemistry. Results:, The results indicated that rat FLT3 cDNA has high homology with mouse and human FLT3 cDNA. It was also found that FLT3 is expressed in most of the rat tissues and during liver regeneration. In addition, its intracellular localization is altered during the late stages of liver regeneration. Conclusion:, The FLT3 receptor is activated at the late stages of liver regeneration and participates in the proliferation response that is observed during progenitor-dependent liver regeneration. [source] Cytotoxic and antimitotic effects of N -containing Monascus metabolites studied using immortalized human kidney epithelial cellsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 4-5 2006Anja Knecht Abstract Recently the first Monascus metabolites with a pyridine ring were detected, the monascopyridines A and B. They are formally dehydrogenated derivatives of the red rice pigments rubropunctamine and monascorubramine. Because of their structural similarity, the toxicological effects of these secondary metabolites were studied using immortalized human kidney epithelial cells. The cytotoxicity was determined with the following different endpoint detection methods: metabolic activity, trypan blue exclusion, and electronic cell counting. The compounds led to EC50 values between 11 and 31 ,mol/L but the pigments caused a stronger reduction of the cell viability. Also, the apoptotic potential was examined by measuring caspase 3 activity and detecting apoptotic bodies, but none of the tested compounds induced apoptosis. All four substances caused a rise of the mitotic index to about 9% (100 ,mol/L monascopyridine A and B) and 20% (25 ,mol/L rubropunctamine and monascorubramine). The significant decrease of the ratio of cells in the ana- and telophase to cells in the prometa- and metaphase proved a stop of the mitosis at the meta- to anaphase control point. The compounds caused mitotic arrest and the formation of structural damages like c-mitosis through interaction with the mitotic spindle. These effects point to an aneuploidy inducing potential, which is linked to cancer formation. [source] Adult neural stem cells and their role in brain pathology,THE JOURNAL OF PATHOLOGY, Issue 2 2009G Yadirgi Abstract Stem cells are multipotent cells that can give rise to a differentiated progeny as well as self-renew. The balanced coordination of these two stem cell fates is essential for embryonic development and tissue homeostasis in the adult. Perturbed stem cell function contributes significantly to a variety of pathological conditions, eg impaired self-renewal capacity due to cellular senescence contributes to ageing, and degenerative diseases or impaired stem cell differentiation by oncogenic mutations contribute to cancer formation. This review focuses on the molecular mechanisms involved in regulating the normal function of neural stem cells in the adult mammalian brain and on the involvement of these cells in brain pathology. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] | |||||||||||||