Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.
Previous studies showed that i.p. administration of C75, a potent inhibitor of fatty acid synthase (FAS), blocked fasting-induced up-regulation of orexigenic neuropeptides and down-regulation of anorexigenic neuropeptides in the hypothalami of mice. As a result, food intake and body weight were drastically reduced. Here we provide evidence supporting the hypothesis that hypothalamic malonyl-CoA, a substrate of FAS, is an indicator of global energy status and mediates the feeding behavior of mice. We use a sensitive recycling assay to quantify malonyl-CoA to show that the hypothalamic malonyl-CoA level is low in fasted mice and rapidly (<2 h) increases (Ϸ5-fold) on refeeding. Intracerebroventricular C75 ͉ acetyl-CoA carboxylase ͉ fatty acid synthase ͉ neuropeptides ͉ obesity T he hypothalamus monitors global energy status in higher animals (1-4). Specific regions within the hypothalamus, notably the arcuate nucleus, respond to changes in energy status by altering the expression͞secretion of neuropeptides that affect energy intake and expenditure. Thus, when energy intake exceeds expenditure expression of the orexigenic neuropeptides, i.e., NPY and AgRP, decreases whereas the expression of anorexigenic neuropeptides, i.e., proopiomelanocortin (POMC) and CART, increases (1). Signals triggered by these changes are transmitted to higher brain centers through second-order neurons that affect behavior leading to decreased food intake. Conversely, when energy expenditure exceeds intake, the inverse response occurs. Despite considerable progress in identifying many of the neuropeptides and circuits involved (1-4), the signaling mechanisms by which energy status is initially monitored by neurons of the hypothalamus are incompletely understood.Recent evidence (5, 6) has implicated malonyl-CoA, an intermediate in fatty acid biosynthesis, as a possible mediator in the hypothalamic signaling pathway that monitors energy status. We and others have detected both acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (6, 7), enzymes that catalyze the formation and utilization of malonyl-CoA, respectively, in a subset of hypothalamic neurons. A potent inhibitor of FAS, i.e., C75 (8), that would be expected to increase cellular malonyl-CoA, suppresses food intake and appropriately alters expression of the hypothalamic neuropeptide mRNAs described above (9). Also consistent with the ''malonyl-CoA hypothesis'' is a recent report of Gilbert et al. (10), who found that carotid infusion of obese (Zucker) rats with glucose and insulin suppressed food intake and this effect was prevented by the ACC inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), administered intracerebroventricularly (i.c.v.). Although these indirect lines of evidence support the hypothesis that malonyl-CoA participates in monitoring energy status in the hypothalamus, direct proof is still lacking.Most previous studies (5-7, 9, 11) compared the effects of C75 administered by i.p. injection to mice that had been fasted to increase appetite when presented with food....
Central nervous system control of energy balance affects susceptibility to obesity and diabetes, but how fatty acids, malonyl-CoA, and other metabolites act at this site to alter metabolism is poorly understood. Pharmacological inhibition of fatty acid synthase (FAS), rate limiting for de novo lipogenesis, decreases appetite independently of leptin but also promotes weight loss through activities unrelated to FAS inhibition. Here we report that the conditional genetic inactivation of FAS in pancreatic β cells and hypothalamus produced lean, hypophagic mice with increased physical activity and impaired hypothalamic PPARα signaling. Administration of a PPARα agonist into the hypothalamus increased PPARα target genes and normalized food intake. Inactivation of β cell FAS enzyme activity had no effect on islet function in culture or in vivo. These results suggest a critical role for brain FAS in the regulation of not only feeding, but also physical activity, effects that appear to be mediated through the provision of ligands generated by FAS to PPARα. Thus, 2 diametrically opposed proteins, FAS (induced by feeding) and PPARα (induced by starvation), unexpectedly form an integrative sensory module in the central nervous system to orchestrate energy balance. IntroductionHigher organisms adapt to changes in energy needs by assimilating peripheral hormonal and nutritional cues and integrating them in the central nervous system (1, 2). Even subtle defects in this system have deleterious consequences since modest excess weight in humans is associated with increased mortality (3, 4). The most thermodynamically efficient strategy for weight loss is appetite suppression, a difficult goal given the diversity of factors regulating food intake, ranging from amines and peptides to metabolites and fatty acids (reviewed in ref. 5).Fatty acid metabolism affects feeding behavior. Malonyl-CoA, an intermediary substrate controlling fatty acid flux, and carnitine palmitoyltransferase-1 (CPT-1), which allows fatty acids access to mitochondria for β-oxidation, have been independently implicated in regulating appetite (6, 7). Pharmacological inhibition of fatty acid synthase (FAS), the multifunctional enzyme that utilizes malonyl-CoA for the first committed step in fatty acid biosynthesis (8), with the compound C75 produces anorexia and weight loss in mice in the setting of increased malonyl-CoA (9). However, recent studies indicate that these effects on malonyl-CoA alone may not be sufficient to induce anorexia, as C75 also has an impact on the sympathetic nervous system and metabolic mediators, including PPARα and PPARγ coactivator-1 α (PGC1α) (10, 11). In addition,
Metastasis is a complex multistep process that involves critical interactions between cancer cells and a variety of stromal components in the tumor microenvironment, which profoundly influence the different aspects of the metastatic cascade and organ tropism of disseminating cancer cells. Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Evidence has demonstrated that ovarian cancer possesses specific metastatic tropism for the adipose-rich omentum, which has a pivotal role in the creation of the metastatic tumor microenvironment in the intraperitoneal cavity. Considering the distinct biology of ovarian cancer metastasis, the elucidation of the cellular and molecular mechanisms underlying the reciprocal interplay between ovarian cancer cells and surrounding stromal cell types in the adipose-rich metastatic microenvironment will provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer. Herein, we review the biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum by illustrating how different stromal cells concertedly contribute to the development of ovarian cancer metastasis and metastatic tropism for the omentum.
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