Origins of Cancer

Project Leader: Dr Jeff Holst

The importance of lifestyle and environmental factors on development of disease has long been a focus of biomedical research and media attention. Diet in particular is implicated in many different diseases, however measuring the effects of nutrition on disease has been limited. It is known that the expression of specific amino acid transporters is increased in many primary cancers, and indeed there is growing literature that obesity can be linked with diabetes, cardiovascular disease and cancer.

Tumours require a constant supply of nutrients in order to maintain their growth advantage and it has been shown that cancer cells consume more nutrients than normal cells. Scientists are now discussing the "tumour metabolome", the characterisation of which will provide increased understanding of how the metabolic requirements of tumours may lead to new treatments for cancer.

Over the last decade, drugs designed to block blood vessel formation have provided an entirely new string to the cancer treatment bow. There are over 350 different nutrient transporters, which can transport a variety of substrates, including amino acids. In this project we propose an exciting and novel extension derived from these observations: just like anti-angiogenic therapies, a new approach to anticancer therapeutics may include nutrient uptake inhibitors.

Major projects

The role of amino acid transport in prostate cancer
The PI3K/PTEN/Akt pathway is frequently altered in prostate cancer. Up and down-regulation of many members of this pathway, including mTOR, neutral endopeptidase and PTEN, together or separately, are found in most prostate cancers.

Amino acids such as leucine have been shown to activate mTOR thereby contributing to uncontrolled proliferation of prostate cancer cells. The host laboratory's international track record in amino acid regulation will be applied to dissect how transporters including leucine transporters, may promote prostate cancer.

This will be studied using prostate cancer cell lines and a prostate cancer mouse model crossed with a new knockout mouse model. Analysis of the genes involved in the onset and progression of prostate cancer will be determined in these models. POV1 transporter is a potential target for therapeutic intervention, and understanding this complex network may provide new insights into the effect of diet (particularly red meats and dairy which are high in leucine) on the development and progression of prostate cancer.

Publications

1. Holst J, Wang H, Durick Eder K, Workman CJ, Boyd KL, Baquet Z, Singh H, Forbes K, Chruscinski A, Smeyne R, van Oers NSC, Utz PJ, Vignali DAA. Scalable signaling mediated by T cell antigen receptor - CD3 ITAM ensures effective negative selection and prevents autoimmunity. Nature Immunology 9, 658-666, 2008.

2. Holst J, Vignali K, Burton AR, Vignali DAAV. Rapid analysis of T cell selection in vivo using T cell receptor retrogenic mice. Nature Methods 3(3), 191-197, 2006.

3. Holst J, Szymczak-Workman AL, Vignali KM, Burton AR, Workman CJ, Vignali DAAV. Generation of T cell receptor retrogenic mice. Nature Protocols 1(1), 406-417, 2006.

4. El Kasmi KC, Holst J, Coffre M, Mielke L, de Pauw A, Lhocine N, Smith AM, Rutschman R, Kaushal D, Shen Y, Suda T, Donnelly RP, Myers Jr. MG, Alexander W, Vignali DAA, Watowich SS, Ernst M, Hilton DJ, Murray PJ. General nature of the STAT3-activated anti-inflammatory response. Journal of Immunology 177: 7880-7888, 2006.

5. Holst J, Sim AT, Ludowyke RI. Protein phosphatases 1and 2A transiently associate with myosin during the peak rate of secretion from mast cells. Molecular Biology of the Cell 13:1083-1098, 2002.

For more publication information, please contact Dr Holst or search the available listings on PubMed.