Use of biofluids and a unique inducible/reversible mouse model of aggressive neoplasia to test for cancer biomarkers.
EMSL Project ID
30478
Abstract
The early diagnosis of cancers is central to successful treatment as current therapies work most effectively with early stages of the disease. As a result there has been much recent emphasis on screening for biomarkers using proteomic and gene approaches. Metabolites provide an alternate but less well researched type of biomarker that may also be detected in biofluids. These metabolites can act as sentinels of cellular diseased state as demonstrated by the use of increased glucose as a measure of pancreatic function in diabetes. Recent work, building on data generated by Otto Warburg over 70 years ago, demonstrates that cancer cells show increased rates of metabolism and rapidly adapt to changes in nutritional and environmental states (e.g. hypoxia). Importantly these cells have increased rates of glucose consumption and de novo lipid production. In our preliminary NMR work with EMSL we have demonstrated that c-Myc, a transcription factor and pervasive oncogene deregulated in over 50% of human cancers, can also regulate the partitioning of glucose carbons to multiple metabolic pathways. Myc activation can thereby rapidly increased the lipid, amino acid, ribonucleotides and C1/folate metabolites required for rapid cell proliferation. In the current proposal we would like to build on this knowledge and use a unique model of  cell neoplasia, which is dependent on the expression of an inducible MycER protein in a p53 null mouse background, to study changes in metabolite profiles from the biofluids urine and serum. In this model, highly aggressive and invasive tumors develop rapidly and synchronously within 21 days on induction of MycER using 4-hydroxytamixifen. In the absence of tamoxifen the tumor regresses within 16 days. Hence, this model provides an ideal system in which to study the metabolic changes arising in biofluids during cancer progression and regression. In this way this proposal is will address some of the key questions of interest to EMSL, which include the analysis of cellular response to environment and changes arising over time in response to alterations in gene expression in biological systems. We expect that metabolic profiling of this inducible model may uncover unique profiles that are indicative of the development of aggressive tumors. Our specific aims in this study are 1) to perform preliminary experiments to develop reproducible LC-NMR methods for the assessment of mouse biofluids and 2) to perform metabolite screens of serum and urine both during induction and regression of -cell neoplasias in MycER/p53 null mice. Results from this work will provide profiles of metabolites that are altered during both the development and regression of aggressive tumors. These data may potentially uncover novel metabolic biomarkers indicative of cancer development.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2008-10-01
End Date
2011-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members