Frequent polymorphism of peroxisome proliferator activated receptor γ gene in colorectal cancer containing wild-type K-ras gene

Author(s):  
S. Tomita ◽  
H. Kawamata ◽  
J. Imura ◽  
F. Omotehara ◽  
Y. Ueda ◽  
...  
2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15084-e15084
Author(s):  
L. Xie ◽  
R. Lai ◽  
X. Wu ◽  
S. Zhang ◽  
X. Tang ◽  
...  

e15084 Background: Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We follow -up study the efficacy and toxicity of cetuximab with chemotherapy in the treatment of advanced colorectal cancer from Chinese in East China. Methods: We analyzed tumor samples from 120 patients with advanced colorectal cancer by direct sequencing, to observe the mutations status in exon 2,3 of K-ras gene. And 30 patients were followed up according the RECIST standard for their treatment outcome of cetuximab plus chemotherapy at 2 -12 months. Results: K-ras mutations were identified in 48 of 120(40%) patients with colorectal cancer in exon2, which including 8 mutation types; 38/48(79.2%) mutations in 12 codon(G12D 43.7%,G12V 25%,G12C 10.4%,G12R 6%,G12S 4%,G12A 2%) and 10/48(18.7%) in 13 codon(G13D 18.7%,G13C 2%). None mutation was found in 61codon of exon3. we observed the clinical efficacy of 30 patients treated by cetuximab plus chemotherapy, of 21 patients with wild-type K-ras tumors as compared with 9 patients with mutated K-ras significantly improved the response rate (5/21 21.8% vs 1/9 11.1%,P<0.01)and the disease control rate (19/21 90.4% vs,2/9 22.2%,P<0.01). There were a few patients with mutated K-ras tumors benefit from cetuximab, in which the fluorescence intensity of mutation cells of all detected tumor tissue approach to 1:3 status by sequencing analysis. The major toxicities of treatment were acne-like rash, which were found in 14/21(66.6%)of patients with wild-type K- ras, and 5/9(55.5%)of patients with mutated K-ras . Conclusions: The East-China patients share the same (40%) mutation frequency and type of k-ras gene with other races . Patients with wild type K-ras mutation have significantly higher Response rate and disease control rate on cetuximab plus chemotherapy treatment .Our results once again show that somatic mutations status of k-ras is a major determinant of cetuximab response in advanced colorectal cancer. There was no statistical correlation between acne-like rash of the major toxicities and mutations status of k-ras. There were a few patients bearing mutated k-ras did benefit from cetuximab, that would need to be validation between Chinese or Ethnicity association phenotype by a large numbers of samples. No significant financial relationships to disclose.


Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2176-2183 ◽  
Author(s):  
Bianca Hemmeryckx ◽  
Rita van Bree ◽  
Berthe Van Hoef ◽  
Lisbeth Vercruysse ◽  
H. Roger Lijnen ◽  
...  

Pregnancy-induced metabolic changes are regulated by signals from an expanded adipose organ. Placental growth factor (PlGF), acting through vascular endothelial growth factor receptor-1, may be among those signals. There is a steep rise in circulating PlGF during normal pregnancy, which is repressed in gravidas who develop preeclampsia. PlGF-deficiency in mice impairs adipose vascularization and development. Here we studied young-adult PlGF-deficient (PlGF−/−) and wild-type mice on a high-fat diet in the nongravid state and at embryonic day (E) 13.5 or E18.5 of gestation. Litter size and weight were normal, but E18.5 placentas were smaller in PlGF−/− pregnancies. PlGF−/− mice showed altered intraadipose dynamics, with the following: 1) less blood vessels and fewer brown, uncoupling protein (UCP)-1-positive, adipocytes in white sc and perigonadal fat compartments and 2) white adipocyte hypertrophy. The mRNA expression of β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1 was decreased accordingly. Moreover, PlGF−/− mice showed hyperinsulinemia. Pregnancy-associated changes were largely comparable in PlGF−/− and wild-type dams. They included expanded sc fat compartments and adipocyte hypertrophy, whereas adipose expression of key angiogenesis/adipogenesis (vascular endothelial growth factor receptor-1, peroxisome proliferator-activated receptor-γ2) and thermogenesis (β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1) genes was down-regulated; circulating insulin levels gradually increased during pregnancy. In conclusion, reduced adipose vascularization in PlGF−/− mice impairs adaptive thermogenesis in favor of energy storage, thereby promoting insulin resistance and hyperinsulinemia. Pregnancy adds to these changes by PlGF-independent mechanisms. Disturbed intraadipose dynamics is a novel mechanism to explain metabolic changes in late pregnancy in general and preeclamptic pregnancy in particular.


2014 ◽  
Vol 1843 (6) ◽  
pp. 1225-1236 ◽  
Author(s):  
Anna Panza ◽  
Carolina Votino ◽  
Annamaria Gentile ◽  
Maria Rosaria Valvano ◽  
Tommaso Colangelo ◽  
...  

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1706-1716 ◽  
Author(s):  
Fen Xu ◽  
David Burk ◽  
Zhanguo Gao ◽  
Jun Yin ◽  
Xia Zhang ◽  
...  

The histone deacetylase sirtuin 1 (SIRT1) inhibits adipocyte differentiation and suppresses inflammation by targeting the transcription factors peroxisome proliferator-activated receptor γ and nuclear factor κB. Although this suggests that adiposity and inflammation should be enhanced when SIRT1 activity is inactivated in the body, this hypothesis has not been tested in SIRT1 null (SIRT1−/−) mice. In this study, we addressed this issue by investigating the adipose tissue in SIRT1−/− mice. Compared with their wild-type littermates, SIRT1 null mice exhibited a significant reduction in body weight. In adipose tissue, the average size of adipocytes was smaller, the content of extracellular matrix was lower, adiponectin and leptin were expressed at 60% of normal level, and adipocyte differentiation was reduced. All of these changes were observed with a 50% reduction in capillary density that was determined using a three-dimensional imaging technique. Except for vascular endothelial growth factor, the expression of several angiogenic factors (Pdgf, Hgf, endothelin, apelin, and Tgf-β) was reduced by about 50%. Macrophage infiltration and inflammatory cytokine expression were 70% less in the adipose tissue of null mice and macrophage differentiation was significantly inhibited in SIRT1−/− mouse embryonic fibroblasts in vitro. In wild-type mice, macrophage deletion led to a reduction in vascular density. These data suggest that SIRT1 controls adipose tissue function through regulation of angiogenesis, whose deficiency is associated with macrophage malfunction in SIRT1−/− mice. The study supports the concept that inflammation regulates angiogenesis in the adipose tissue.


2005 ◽  
Vol 24 (5) ◽  
pp. 327-339 ◽  
Author(s):  
Carla E. Torrey ◽  
Henry G. Wall ◽  
James A. Campbell ◽  
Puntipa Kwanyuen ◽  
Debie J. Hoivik ◽  
...  

This study was conducted as part of the International Life Sciences Institute (ILSI) Alternatives to Carcinogenicity Testing program and evaluated the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) α agonist following dermal application to transgenic Tg.AC and nontransgenic FVB mice for a minimum of 26 weeks. Clofibrate doses of 12, 28, or 36 mg/200 μl/day were used. Positive controls for papilloma formation were benzene (174.8 mg/200 μl), and 12- o-tetradecanoylphorbol-13-acetate (TPA [0.00250 mg/200 μl]). Clofibrate was tolerated at doses up to 36 mg/200 μl. In Tg.AC mice, clofibrate produced a dose-related increase in the incidence of mice with cutaneous papillomas; and dose-related decreases in mean time to first tumor, mean multiplicity of tumors per mouse, and mean weeks to maximal yield, as well as numerous nonneoplastic microscopic lesions in the liver, kidney, spleen, and skin. Benzene and TPA induced both neoplastic and/or non-neoplastic proliferative lesions in Tg.AC mice. Clofibrate did not increase the incidence or multiplicity of papillomas, or any other tumors in FVB mice. These data show that the Tg.AC dermal model has increased sensitivity in detecting skin papillomas caused by the nongenotoxic rodent carcinogen, clofibrate, compared to wild type FVB mice, at systemic exposures that are 3× higher than the systemic exposure observed in humans taking clofibrate (AUC = 1100 μg ·h/ml) at the recommended maximum therapeutic dose of 500 mg. In addition, this study supports the proposed concept that Tg.AC model may detect compounds with nongenotoxic carcinogenic potential in a shorter timeframe than conventional mouse carcinogenicity bioassays.


2002 ◽  
Vol 364 (2) ◽  
pp. 361-368 ◽  
Author(s):  
Mary C. SUGDEN ◽  
Karen BULMER ◽  
Geoffrey F. GIBBONS ◽  
Brian L. KNIGHT ◽  
Mark J. HOLNESS

The aim of the present study was to determine whether peroxisome-proliferator-activated receptor-α (PPARα) deficiency disrupts the normal regulation of triacylglycerol (TAG) accumulation, hepatic lipogenesis and glycogenesis by fatty acids and insulin using PPARα-null mice. In wild-type mice, hepatic TAG concentrations increased (P<0.01) with fasting (24h), with substantial reversal after refeeding (6h). Hepatic TAG levels in fed PPARα-null mice were 2.4-fold higher than in the wild-type (P<0.05), increased with fasting, but remained elevated after refeeding. PPARα deficiency also impaired hepatic glycogen repletion (P<0.001), despite normal insulin and glucose levels after refeeding. Higher levels of plasma insulin were required to support similar levels of hepatic lipogenesis de novo (3H2O incorporation) in the PPARα-null mice compared with the wild-type. This difference was reflected by corresponding changes in the relationship between plasma insulin and the mRNA expression of the lipogenic transcription factor sterol-regulatory-element-binding protein-1c, and that of one of its known targets, fatty acid synthase. In wild-type mice, hepatic pyruvate dehydrogenase kinase (PDK) 4 protein expression (a downstream marker of altered fatty acid catabolism) increased (P<0.01) in response to fasting, with suppression (P<0.001) by refeeding. Although PDK4 up-regulation after fasting was halved by PPARα deficiency, PDK4 suppression after refeeding was attenuated. In summary, PPARα deficiency leads to accumulation of hepatic TAG and elicits dysregulation of hepatic lipid and carbohydrate metabolism, emphasizing the importance of precise control of lipid oxidation for hepatic fuel homoeostasis.


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