Home About us Contact
|
Home About us Contact | ||
|
|
||
Tumor Proliferation (tumor + proliferation)
Selected AbstractsThe effect of thiamine supplementation on tumour proliferationFEBS JOURNAL, Issue 15 2001A metabolic control analysis study Thiamine deficiency frequently occurs in patients with advanced cancer and therefore thiamine supplementation is used as nutritional support. Thiamine (vitamin B1) is metabolized to thiamine pyrophosphate, the cofactor of transketolase, which is involved in ribose synthesis, necessary for cell replication. Thus, it is important to determine whether the benefits of thiamine supplementation outweigh the risks of tumor proliferation. Using oxythiamine (an irreversible inhibitor of transketolase) and metabolic control analysis (MCA) methods, we measured an in vivo tumour growth control coefficient of 0.9 for the thiamine-transketolase complex in mice with Ehrlich's ascites tumour. Thus, transketolase enzyme and thiamine clearly determine cell proliferation in the Ehrlich's ascites tumour model. This high control coefficient allows us to predict that in advanced tumours, which are commonly thiamine deficient, supplementation of thiamine could significantly increase tumour growth through transketolase activation. The effect of thiamine supplementation on tumour proliferation was demonstrated by in vivo experiments in mice with the ascites tumour. Thiamine supplementation in doses between 12.5 and 250 times the recommended dietary allowance (RDA) for mice were administered starting on day four of tumour inoculation. We observed a high stimulatory effect on tumour growth of 164% compared to controls at a thiamine dose of 25 times the RDA. This growth stimulatory effect was predicted on the basis of correction of the pre-existing level of thiamine deficiency (42%), as assayed by the cofactor/enzyme ratio. Interestingly, at very high overdoses of thiamine, ,,2500 times the RDA, thiamine supplementation had the opposite effect and caused 10% inhibition of tumour growth. This effect was heightened, resulting in a 36% decrease, when thiamine supplementation was administered from the 7th day prior to tumour inoculation. Our results show that thiamine supplementation sufficient to correct existing thiamine deficiency stimulates tumour proliferation as predicted by MCA. The tumour inhibitory effect at high doses of thiamine is unexplained and merits further study. [source] Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion,,HEPATOLOGY, Issue 3 2010Wei Ding Epithelial-to-mesenchymal transition (EMT) is predicted to play a critical role in metastatic disease in hepatocellular carcinoma. In this study, we used a novel murine model of EMT to elucidate a mechanism of tumor progression and metastasis. A total of 2 × 106 liver cells isolated from Ptenloxp/loxp/Alb-Cre+ mice, expanded from a single CD133+CD45, cell clone, passage 0 (P0), were sequentially transplanted to obtain two passages of tumor cells, P1 and P2. Cells were analyzed for gene expression using microarray and real-time polymerase chain reaction. Functional analysis included cell proliferation, migration, and invasion in vitro and orthotopic tumor metastasis assays in vivo. Although P0, P1, and P2 each formed tumors consistent with mixed liver epithelium, within the P2 cells, two distinct cell types were clearly visible: cells with epithelial morphology similar to P0 cells and cells with fibroblastoid morphology. These P2 mesenchymal cells demonstrated increased locomotion on wound healing; increased cell invasion on Matrigel basement membrane; increased EMT-associated gene expression of Snail1, Zeb1, and Zeb2; and down-regulated E-cadherin. P2 mesenchymal cells demonstrated significantly faster tumor growth in vivo compared with P2 epithelial counterparts, with invasion of intestine, pancreas, spleen, and lymph nodes. Furthermore, P2 mesenchymal cells secreted high levels of hepatocyte growth factor (HGF), which we propose acts in a paracrine fashion to drive epithelial cells to undergo EMT. In addition, a second murine liver cancer stem cell line with methionine adenosyltransferase 1a deficiency acquired EMT after sequential transplantations, indicating that EMT was not restricted to Pten-deleted tumors. Conclusion: EMT is associated with a high rate of liver tumor proliferation, invasion, and metastasis in vivo, which is driven by HGF secreted from mesenchymal tumor cells in a feed-forward mechanism. (HEPATOLOGY 2010) [source] EBAG9 is a tumor-promoting and prognostic factor for bladder cancerINTERNATIONAL JOURNAL OF CANCER, Issue 4 2009Jinpei Kumagai Abstract Upregulation of EBAG9 expression has been observed in several malignant tumors such as advanced breast and prostate cancers, indicating that EBAG9 may contribute to tumor proliferation. In the present study, we assess the role of EBAG9 in bladder cancer. We generated human bladder cancer EJ cells stably expressing FLAG-tagged EBAG9 (EJ-EBAG9) or empty vector (EJ-vector), and investigated whether EBAG9 overexpression modulates cell growth and migration in vitro as well as the in vivo tumor formation of EJ transfectants in xenograft models of BALB/c nude mice. EBAG9 overexpression promoted EJ cell migration, while the effect of EBAG9 to cultured cell growth was rather minimal. Tumorigenic experiments in nude mice showed that the size of EJ-EBAG9-derived tumors was significantly larger than EJ-vector-derived tumors. Loss-of-function study for EBAG9 using small interfering RNA (siRNA) in xenografts with parental EJ cells showed that the intra-tumoral injection of EBAG9 siRNA markedly reduced the EJ tumor formation compared with control siRNA. Furthermore, immunohistochemical study for EBAG9 expression was performed in 60 pathological bladder cancer specimens. Intense and diffuse cytoplasmic immunostaining was observed in 45% of the bladder cancer cases. Positive EBAG9 immunoreactivity was closely correlated with poor prognosis of the patients (p = 0.0001) and it was an independent prognostic predictor for disease-specific survival in multivariate analysis (p = 0.003). Our results indicate that EBAG9 would be a crucial regulator of tumor progression and a potential prognostic marker for bladder cancer. © 2008 Wiley-Liss, Inc. [source] Antitumor and Antiangiogenic Activity of Soy Phytoestrogen on 7,12-Dimethylbenz[,]anthracene-Induced Mammary Tumors Following Ovariectomy in Sprague,Dawley RatsJOURNAL OF FOOD SCIENCE, Issue 7 2009Xinmei Kang ABSTRACT:, Soy phytoestrogen is often used as hormone replacement therapy to alleviate the symptoms of menopause in postmenopausal women. Since estrogen has been considered as an important risk factor for the development of breast carcinoma, we need to know whether it is safe for these postmenopausal women with breast cancer to take soy foods that are rich in phytoestrogen. In the present study, we investigated the efficacy of soy phytoestrogen on tumor proliferation, apoptosis, and angiogenesis in mammary tumors that had already formed in ovariectomized rats. We found that soy phytochemical extraction inhibited proliferation and induced apoptosis,in vitro,and,in vivo, and it demonstrated better antitumor effects than single phytoestrogen. Soy phytochemical extraction also produced surprisingly good antiangiogenic effects, which were evidenced by lower microvascular density, reduced plasma vascular endothelial growth factor, and increased plasma endostatin levels. Our findings suggest that soy phytochemical extraction exerts significant antitumor and antiangiogenic activity in a postmenopausal animal model with breast cancer. [source] Role of cyclooxygenase-2 and inducible nitric oxide synthase in pancreatic cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2002Gu Kong Abstract Background and Aim: Recently, it has been recognized that both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) produce important endogenous factors of human tumor progression. However, the clinicopathological and biological significance of the expression of COX-2 and iNOS in pancreatic cancer remains unclear. The objective of this study is to find the possible roles and clinical significance of COX-2 and iNOS expression in pancreatic cancer. Methods: Seventy-two pancreatic adenocarcinoma tissue specimens were obtained through surgical resection. We investigated the immunohistochemical expression of COX-2 and iNOS in respect to variable clinicopathological characteristics, proliferation activity (by Ki-67 expression), apoptosis (by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling stain), and microvessel density (by CD34 expression; angiogenesis). Results: Immunohistochemical investigations demonstrated immunolabeling of tumor cells with the primary antibodies, bovine anti-iNOS and anti-COX-2 antibodies. The COX-2 and iNOS positive rates were 41.7 and 66.7%, respectively. There was significant correlation between positive COX-2 and positive iNOS expression (P = 0.043). The proliferation index (Ki-67 labeling index) was higher in COX-2 positive specimens compared to COX-2 negative specimen (P = 0.015). The apoptotic index of positive iNOS expressions was significantly higher than negative expressions (P < 0.001). The expression of COX-2 and iNOS proteins did not correlate with age, sex, serum bilirubin, CA-19,9, location, size, American Joint Committee on Cancer stage, differentiation, distant metastasis, patient survival, or microvessel density. Conclusions: Although the pattern of positive expression was similar in both enzymes, the effect on tumor progression differed; iNOS expression may play a role in apoptosis of tumor cell, while COX-2 expression may contribute to tumor proliferation. However, COX-2 and iNOS expression is not related to prognosis in patients with pancreatic cancer. © 2002 Blackwell Publishing Asia Pty Ltd [source] Imaging the proliferative status of tumors with PET ,JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 5-6 2007Robert H. Mach Abstract The development of radiotracers for imaging solid tumors has recently focused on measuring a tumor's proliferative status. Two different strategies have emerged: (1) radiolabeled DNA precursors that measure DNA synthesis; and (2) radiotracers that label the sigma-2 receptor, a putative biomarker of proliferation. This paper provides a brief description of these two different methods of imaging tumor proliferation that are currently being developed in the field of positron emission tomography (PET). Copyright © 2007 John Wiley & Sons, Ltd. [source] Co-regulation of B-Myb expression by E2F1 and EGF receptor,MOLECULAR CARCINOGENESIS, Issue 1 2006Norihisa Hanada Abstract Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is frequently over-expressed in human cancers and is associated with tumorigenesis, and increased tumor proliferation and progression. Also found in breast tumors with high levels is B-Myb, a transcription factor whose expression is activated by E2F1/3 at the late G1 phase and the level is sustained through the S phase. Recent reports suggest a casual correlation between EGFR and B-Myb expression in primary breast carcinomas. However, the mechanism for such co-expression remains un-investigated. Here, we report that EGFR is important for B-Myb expression and the underlying mechanism involves cooperated effects from EGFR and E2F1. EGF stimulation and forced expression of EGFR significantly increase B-Myb gene activity and such increase occurs in the G1 phase. EGF-induced B-Myb expression was not significantly suppressed following inhibition of PI-3K and ERK, two major EGFR downstream pathways. In contrast, we observed EGF-induced in vivo association of nuclear EGFR to the B-Myb promoter and the association is only detected at the G1/S phase and is abolished by EGFR kinase inhibitor. As EGFR lacks DNA-binding domain but contains transactivational activity and E2F1 activates B-Myb expression in the G1/S phase, we further reasoned that nuclear EGFR might cooperate with E2F1 leading to activation of B-Myb. Indeed, we found that EGFR co-immunoprecipitated with E2F1 in an EGF-dependent manner and that EGF activated in vivo binding of E2F1 to the B-Myb promoter. Consistently, forced expression of both EGFR and E2F1 in EGFR-null CHO cells greatly enhanced B-Myb promoter activity, compared to the vector control and expression of EGFR or E2F1 alone. Promoter mutagenesis studies showed that EGF-induced activation of B-Myb promoter required both E2F and EGFR target sites. In summary, our data suggest that deregulated EGFR signaling pathway facilitate tumor cell proliferation partly via EGFR interaction with E2F1 and subsequent activation of B-Myb gene expression. © 2005 Wiley-Liss, Inc. [source] Antitumor activity of chloroform fraction of Scutellaria barbata and its active constituentsPHYTOTHERAPY RESEARCH, Issue 9 2007Jianqing Yu Abstract Scutellaria barbata (SB) is widely used as an antitumor agent in China, but the antitumor components of SB are still unclear. The antitumor activity of various fractions of an ethanol extract of SB was studied in six human malignant cell lines. Bio-based assays showed that non-polar and low-polar solvent fractions of SB had dose-dependent cytotoxicities on six cancer cell lines. The IC50 values of these fractions on the cancer cell lines tested ranged from 16 to 70 µg/mL after 48 h of treatment. Among them, the chloroform fraction (CE-SB) had the strongest cytotoxicity on cancer cell lines with a lower cytotoxic effect on a normal liver cell line. Bel-7402 cell apoptosis induced by CE-SB was examined using Hoechst 33258 staining, agarose gel electrophoresis and flow cytometry. CE-SB dose-dependently decreased the S phase content. Treatment with CE-SB caused cytochrome c release and activation of caspase-9. The antitumor activity of CE-SB in vivo was also evaluated. At 60 mg/kg/day, CE-SB significantly inhibited the solid tumor proliferation and increased the life span of ascites tumor bearing mice (p < 0.01). CE-SB was subjected to bioassay-guided isolation of the active compounds by chromatography on silica gel and Sephadex LH-20. Phytol, wogonin, luteolin and hispidulin were obtained as cytotoxic constituents. Copyright © 2007 John Wiley & Sons, Ltd. [source] Human-in-mouse modeling of primary head and neck squamous cell carcinoma,THE LARYNGOSCOPE, Issue 12 2009Jonathan H. Law MD Abstract Objectives/Hypothesis: To develop a reliable modeling system for head and neck squamous cell carcinoma (HNSCC). Study Design: Laboratory-based translational study. Methods: HNSCC tissue was obtained from patients at biopsy/resection, cultured, and implanted into mice. In vivo, tumor growth, and survival was monitored by bioluminescence imaging. Histology and immunohistochemistry (IHC) were used to confirm HNSCC and human origin. Results: Short-term culture techniques were optimized allowing survival of primary HNSCC cells more than 7 days in 76% of tumors. The size of the tumor biopsy collected did not correlate with the success of short-term culture or xenograft establishment. Xenograft modeling was attempted in primary HNSCCs from 12 patients with a success rate of 92%. Immunostaining confirmed human origin of epithelial tumor cells within the modeled tumor. Bioluminescence and Ki67 IHC suggested tumor proliferation within the model. Luciferase expression was maintained for as long as 100 days in modeled tumors. Conclusions: The techniques developed for short-term primary tumor culture followed by xenograft modeling provide a low-cost and tractable model for evaluation of HNSCC response to standard and novel therapies. The high success rate of human-in-mouse tumor formation from primary HNSCC suggests that selection pressures for tumor growth in this model may be less than those observed for establishment of cell lines. Bioluminescent imaging provides a useful tool for evaluating tumor growth and could be expanded to measure response of the modeled tumor to therapy. This model could be adapted for xenograft modeled growth of other primary tumor types. Laryngoscope, 2009 [source] Angiogenesis in patients with craniopharyngiomasCANCER, Issue 3 2002Correlation with treatment, outcome Abstract BACKGROUND Craniopharyngiomas are histologically benign epithelial neoplasms of the sellar region that often exhibit aggressive and invasive growth. The authors hypothesized that tumor proliferation, spread, and recurrence are angiogenesis dependent and investigated the significance of vascularization relative to biologic behavior. To the authors' knowledge, angiogenesis for patients with craniopharyngiomas has not been examined to date. METHODS The authors measured microvessel densities in resected, histologically proven craniopharyngiomas using immunostains for CD-34, a monoclonal antibody that selectively recognizes endothelial cells. Both histologic types of craniopharyngiomas, adamantinomatous and papillary, were included in the study. In addition, the cellular distribution of vascular endothelial growth factor (VEGF), a strong stimulator of new vessel formation, was assessed by both immunohistochemistry and in situ hybridization for VEGF receptor 2 (VEGFR-2) mRNA expression. RESULTS Histologically, small numbers of capillaries were identified in temporal stroma but not in their epithelial components. Immunohistochemistry revealed strong, conclusive cytoplasmic immunoreactivity for VEGF in the epithelial cells of both adamantinomatous craniopharyngiomas and papillary craniopharyngiomas. In situ hybridization showed that VEGFR-2 mRNA was expressed widely, not only in neoplastic epithelium but also in capillary endothelium. CONCLUSIONS Tumors with greater microvessel density regrow more frequently compared with tumors that have lower microvessel density, suggesting that the extent of angiogenesis is of prognostic value in patients with craniopharyngioma. VEGFR-2 may act as a key modulator of VEGF activity in endothelial cells and nonendothelial cells, indicating that VEGF plays an important role in the behavior of craniopharyngiomas. Cancer 2002;94:738,45. © 2002 American Cancer Society. DOI 10.1002/cncr.10281 [source] | |||||||||||||