[On the transformation of embryonal metabolism into cancer metabolism].
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Neuroendocrine (NE) cancers occur in multiple anatomic locations and range in prognosis from indolent to aggressive. In addition, adenocarcinomas can express gene products associated with NE cells, referred to as NE differentiation (NED), which correlates with poor prognosis and aggressive disease. Several metabolites and peptides produced by NE cells have been discovered that engage in cellular signaling and have autocrine and paracrine effects on cancer cell proliferation. This review focuses on the current knowledge of small molecule metabolism in NE cancers involving the synthesis of biogenic amine, polyamine, and amino acid neurotransmitters. Systems biology-directed approaches to NE cancer metabolism using gene expression profiling, liquid chromatography/mass spectrometry (LC/MS) and nuclear magnetic resonance (NMR) are also discussed. Furthermore, knowledge of metabolic and signaling pathways in NE cancers has led to the successful implementation of therapeutic regimens in cell culture and animal models of NE carcinogenesis.
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High levels of fecal bile acids have been associated with populations at high risk for developing colon cancer. In this study, 168 subjects were drawn from populations that show low and high mortality from colon cancer [pure vegetarians, lacto-ovo vegetarians, and nonvegetarians Seventh-day Adventists (SDA) and demographically comparable group from the general population]. Lyophilized aliquots of 3-day stool samples were examined for levels of primary (cholic and chenodeoxycholic acids) and secondary (deoxycholic and lithocholic acids) bile acids. Total bile acids (mg/g lyophilized stools) were statistically different among dietary groups: SDA pure vegetarians 2.16 +/- 0.32, SDA lacto-ovo vegetarians 3.66 +/- 0.41, SDA nonvegetarians 4.39 +/- 0.44, general population nonvegetarians 6.04 +/- 0.75; but were similar when stool weights, body weights, and fat intake were taken into account. The most striking difference was evident in the ratio of secondary to primary bile acids: when compared to SDA pure vegetarians, both SDA lacto-ovo vegetarians and SDA nonvegetarians had twice the ratio while values for general population nonvegetarians were five to six times. The data indicate that these differences in excretion patterns among dietary groups reveal distinctly characteristic metabolic features associated with diet and lifestyle.
Cholesterol and its metabolites, together with bile acids, are implicated as risk factors in the genesis and progression of colon cancer. This study was designed to determine differences in the neutral sterol composition of stools from four different population groups differing in their dietary habits as well as in their expected rates for colon cancer. Four study groups consisting of 18 Seventh-day Adventist (SDA) pure vegetarians, 50 SDA lacto-ovo vegetarians, 50 SDA nonvegetarians, and 50 general population nonvegetarians were selected from the greater Los Angeles Basin area. Three-day composite stool samples were lyophilized and then analyzed for their neutral sterol composition. Cholesterol excretion values consistently showed an age-dependent peak in 46- to 50-yr age group for the total population, SDA lacto-ovo vegetarian and SDA-nonvegetarian subgroups being the principal contributors to this age-dependent phenomenon. The SDA pure vegetarians exhibited the lowest fecal concentrations and daily excretion of cholesterol as expected since their intake of dietary cholesterol is insignificant. Among the other SDA, regardless of whether they are lacto-ovo vegetarians or nonvegetarians, their cholesterol excretion patterns were similar but higher than in the nonvegetarians from the general population. Since dietary intakes of cholesterol are not significantly different among the two nonvegetarian groups, the differences in excretion values are attributable to differences in colonic metabolism. The ratio of cholesterol/cholesterol metabolites showed generally lower values among nonvegetarians compared to the matched group of lacto-ovo vegetarians. The observation was made that fecal cholesterol and its metabolites tend to be higher among nonvegetarians compared to those in the corresponding vegetarian groups.
PURPOSE: To determine whether cancers of the prostate transition zone (TZ) possess a unique metabolic pattern by which they may be identified at proton magnetic resonance (MR) spectroscopic imaging. MATERIALS AND METHODS: Findings in 40 patients who underwent combined endorectal MR imaging and hydrogen 1 MR spectroscopic imaging before radical prostatectomy and who had TZ tumor identified subsequently at step-section pathologic analysis were retrospectively reviewed. Within this population, a subset of 16 patients whose TZ tumor had a largest diameter of 1 cm or greater and was included in the MR spectroscopic imaging excitation volume was identified. In these 16 patients, the ratios of choline-containing compounds (Cho) and creatine/phosphocreatine (Cr) to citrate (Cit) (ie, [Cho + Cr]/Cit), Cho/Cr, and Cho/Cit were compared in tumor and control tissues. The presence of only Cho and the absence of all metabolites were also assessed. RESULTS: The mean values of (Cho + Cr)/Cit, Cho/Cr, and Cho/Cit were different between TZ cancer and control tissues (P =.001, P =.003, and P =.001, respectively; Wilcoxon signed rank test). Nine (56%) of 16 patients had at least one tumor voxel in which Cho comprised the only detectable peak, while no control voxels showed only Cho (P =.008, McNemar test). The percentage of voxels in which no metabolites were detected did not differ between tumor and control tissues (P =.134, McNemar test). CONCLUSION: TZ cancer has a metabolic profile that is different from that of benign TZ tissue; however, the broad range of metabolite ratios observed in TZ cancer precludes the use of a single ratio to differentiate TZ cancer from benign TZ tissue.
The concept of a glycolytic cancer cell was introduced by Warburg over 70 years ago. This perception has since become the rationale that drives a considerable proportion of basic research on cancer, and it influences the current strategies for the diagnosis, monitoring, and treatment of cancer. Here we review the data from the last 40 years on this issue. We conclude that there is no evidence that cancer cells are inherently glycolytic, but that some tumours might indeed be glycolytic in vivo as a result of their hypoxic environment.
The relationships between fiber consumption and human cancer rates have been examined, together with an analysis of the effects of individual dietary fibers on the experimental induction of large bowel cancer. The human epidemiology indicates an inverse correlation between high fiber consumption and lower colon cancer rates. Cereal fiber sources show the most consistent negative correlation. However, human case-control studies in general fail to confirm any protective effect due to dietary fiber. Case-control studies indicate that if any source of dietary fiber is possibly antineoplastic then it is probably vegetables. These results may mean that purified fibers alone do not inhibit tumor development, whereas it is likely that some other factors present in vegetables are antineoplastic. Experiments in laboratory animals, using chemical induction of large bowel cancer, have in general shown a protective effect with supplements of poorly fermentable fibers such as wheat bran or cellulose. In contrast, a number of fermentable fiber supplements including pectin, corn bran, oat bran, undegraded carageenan, agar, psyllium, guar gum, and alfalfa have been shown to enhance tumor development. Possible mechanisms by which fibers may inhibit colon tumorigenesis include dilution and adsorption of any carcinogens and/or promoters contained within the intestinal lumen, the modulation of colonic microbial metabolic activity, and biological modification of intestinal epithelial cells. Dietary fibers not only bind carcinogens, bile acids, and other potential toxins but also essential nutrients, such as minerals, which can inhibit the carcinogenic process. Fermentation of fibers within the large bowel results in the production of short chain fatty acids, which in vivo stimulate cell proliferation, while butyrate appears to be antineoplastic in vitro. Evidence suggests that if dietary fibers stimulate cell proliferation during the stage of initiation, then this may lead to tumor enhancement. Fermentation also lowers luminal pH, which in turn modifies colonic microbial metabolic acidity, and is associated with increased epithelial cell proliferation and colon carcinogenesis. Because dietary fibers differ in their physiochemical properties it has been difficult to identify a single mechanism by which fibers modify colon carcinogenesis. Clearly, more metabolic and physiological studies are needed to fully define the mechanisms by which certain fibers inhibit while others enhance experimental colon carcinogenesis.
The interplay between rewiring tumor metabolism and oncogenic driver mutations is only beginning to be appreciated. Metabolic deregulation has been described for decades as a bystander effect of genomic aberrations. However, for the biology of malignant cells, metabolic reprogramming is essential to tackle a harsh environment, including nutrient deprivation, reactive oxygen species production, and oxygen withdrawal. Besides the well-investigated glycolytic metabolism, it is emerging that several other metabolic fluxes are relevant for tumorigenesis in supporting redox balance, most notably pentose phosphate pathway, folate, and mitochondrial metabolism. The relationship between metabolic rewiring and mutant genes is still unclear and, therefore, we will discuss how metabolic needs and oncogene mutations influence each other to satisfy cancer cells' demands. Mutations in oncogenes, i.e., PI3K/AKT/mTOR, RAS pathway, and MYC, and tumor suppressors, i.e., p53 and liver kinase B1, result in metabolic flexibility and may influence response to therapy. Since metabolic rewiring is shaped by oncogenic driver mutations, understanding how specific alterations in signaling pathways affect different metabolic fluxes will be instrumental for the development of novel targeted therapies. In the era of personalized medicine, the combination of driver mutations, metabolite levels, and tissue of origins will pave the way to innovative therapeutic interventions.
PURPOSE: To determine, in patients with prostate cancer treated with cryosurgery, whether levels of choline and citrate measured at magnetic resonance (MR) spectroscopy can help discriminate regions of residual tumor from other prostatic tissues and necrosis. MATERIALS AND METHODS: Combined MR imaging and three-dimensional proton spectroscopic imaging were performed in 25 patients (mean age, 69 years) with prostate cancer who underwent cryosurgery. Volume imaging and spectroscopic data were analytically corrected for the reception profile of the endorectal and pelvic phased-array coils. Spectral data were aligned with the MR imaging data and compared with serum prostate-specific antigen levels and biopsy results. RESULTS: Histologically confirmed necrotic tissue (432 voxels) did not demonstrate any observable choline or citrate. The (choline + creatine)/ citrate values in regions of histologically confirmed benign prostatic hyperplasia (0.61 +/- 0.21 [standard deviation], 52 voxels) and cancer (2.4 +/- 1.0, 65 voxels) after cryosurgery were not statistically significantly different from those before therapy but were statistically significantly different from the ratio in necrotic tissue and from each other. The (choline + creatine)/citrate images threshold and overlaid in color on T2-weighted images yielded an estimate of the spatial extent of prostate cancer and benign prostatic hyperplasia. CONCLUSION: Volume MR imaging with MR spectroscopic imaging provided a noninvasive assessment of the presence and location of residual cancer after unsuccessful therapy and helped identify successful cryosurgery in patients who still had an elevated prostate-specific antigen level.