Cancer results from alterations (called mutations) in genes. Two classes of genes are mutated in cancer, genes that promote growth (oncogenes) and genes that stop growth (tumor suppressor genes). Perturbations leading to either the persistent activation of oncogenes or the inactivation of tumor suppressor genes result in cancer. Tuberous Sclerosis Complex 2 (TSC2) is a tumor suppressor gene that, when inactivated, leads to the development of Tuberous Sclerosis Complex disease.

How TSC2 functions in healthy individuals to prevent the development of Tuberous Sclerosis Complex disease is not known. We have discovered that TSC2 regulates a protein that is called HIF (for Hypoxia-Inducible Factor), which is activated in many tumor types. HIF allows cancer cells to survive in adverse conditions.

HIF also controls a protein called VEGF (for Vascular Endothelial Growth Factor). VEGF stimulates the growth of blood vessels. Tumors need nutrients and oxygen (to burn the nutrients) to survive. Nutrients and oxygen are delivered to cells through the blood circulation. Cancer cells depend on the blood circulation to get nutrients and oxygen to survive. Cancer cells have developed strategies to stimulate the growth of blood vessels. Often, these strategies involve the production of VEGF. Interestingly, blocking VEGF can slow down the growth of tumors in humans.

We have discovered that cells with inactivated TSC2 produce 20-fold higher levels of VEGF than normal cells. The production of VEGF is likely to contribute to the development of blood vessels and tumor growth.

In this grant, we propose experiments to understand how mutations in TSC2 result in the activation of HIF and VEGF. A better understanding of the mechanisms involved in this process may help us develop new treatments for patients with Tuberous Sclerosis Complex.