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Recent evidence suggests that metabolic changes play a pivotal role in the biology of cancer and in particular renal cell carcinoma (RCC). Here, a global metabolite profiling approach was applied to characterize the metabolite pool of RCC and normal renal tissue. Advanced decision tree models were applied to characterize the metabolic signature of RCC and to explore features of metastasized tumours. The findings were validated in a second independent dataset. Vitamin E derivates and metabolites of glucose, fatty acid, and inositol phosphate metabolism determined the metabolic profile of RCC. alpha-tocopherol, hippuric acid, myoinositol, fructose-1-phosphate and glucose-1-phosphate contributed most to the tumour/normal discrimination and all showed pronounced concentration changes in RCC. The identified metabolic profile was characterized by a low recognition error of only 5% for tumour versus normal samples. Data on metastasized tumours suggested a key role for metabolic pathways involving arachidonic acid, free fatty acids, proline, uracil and the tricarboxylic acid cycle. These results illustrate the potential of mass spectroscopy based metabolomics in conjunction with sophisticated data analysis methods to uncover the metabolic phenotype of cancer. Differentially regulated metabolites, such as vitamin E compounds, hippuric acid and myoinositol, provide leads for the characterization of novel pathways in RCC.
Plant growth and survival depend on photosynthesis in the leaves. This involves the uptake of carbon dioxide from the atmosphere and the simultaneous capture of light energy to produce organic molecules, which enter metabolism and are converted to many other compounds which then serve as building blocks for biomass growth. Leaves are organs specialised for photosynthetic carbon dioxide fixation. The function of leaves involves many trade-offs which must be optimised in order to achieve effective use of resources and maximum photosynthesis. It is known that the morphology of leaves adjusts to the growth environment of plants and this is important for optimising their function for photosynthesis. However, it is unclear how this adjustment is regulated. The general aim of the work presented in this thesis is to understand how leaf growth and morphology are regulated in the model species Arabidopsis thaliana. Special attention was dedicated to the possibility that there might be internal metabolic signals within the plant which affect the growth and development of leaves. In order to investigate this question, leaf growth and development must be considered beyond the level of the single organ and in the context of the whole plant because leaves do not grow autonomously but depend on resources and regulatory influences delivered by the rest of the plant. Due to the complexity of this question, three complementary approaches were taken. In the first and most specific approach it was asked whether a proposed down-stream component of sucrose signalling, trehalose-6-phosphate (Tre-6-P), might influence leaf development and growth. To investigate this question, transgenic Arabidopsis lines with perturbed levels of Tre-6-P were generated using the constitutive 35S promoter to express bacterial enzymes involved in trehalose metabolism. These experiments also led to an unanticipated project concerning a possible role for Tre-6-P in stomatal function, which is another very important function in leaves. In a second and more general approach it was investigated whether changes in sugar levels in plants affect the morphogenesis of leaves in response to light. For this, a series of metabolic mutants impaired in central metabolism were grown in one light environment and their leaf morphology was analysed. In a third and even more general approach the natural variation in leaf and rosette morphological traits was investigated in a panel of wild Arabidopsis accessions with the aim of understanding how leaf morphology affects leaf function and whole plant growth and how different traits relate to each other. The analysis included measurements of leaf morphological traits as well as the number of leaves in the plant to put leaf morphology in a whole plant context. The variance in plant growth could not be explained by variation in photosynthetic rates and only to a small degree by variation in rates of dark respiration. There were four key axes of variation in rosette and leaf morphology – leaf area growth, leaf thickness, cell expansion and leaf number. These four processes were integrated in the context of whole plant growth by models that employed a multiple linear regression approach. This then led to a theoretical approach in which a simple allometric mathematical model was constructed, linking leaf number, leaf size and plant growth rate together in a whole plant context in Arabidopsis.