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Vascular endothelial growth factor receptor signaling

Institution: University of California, San Francisco
Investigator(s): Timothy Quinn, M.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9KT-0149 Award: $224,500
Subject Area: Cardiovascular Disease
Award Type: New Investigator Awards

Initial Award Abstract
Smoking-related cancers begin when the genetic material in a cell becomes mutated, causing the cell to multiply rapidly. A tiny cluster of cancer cells needs nutrients to grow into a large cancerous tumor. Without additional nutrients, a cluster of cancer cells would usually stop growing. Many cancers get additional nutrients by stimulating the growth of new blood vessels into the cancer, a process called angiogenesis. Cancers stimulate angiogenesis by secreting large amounts of specific hormones or growth factors that cause surrounding blood vessels to grow into the cancer. Therefore one potential treatment for cancer is to block the formation of new blood vessels that would allow the cancer to grow. In essence this amounts to attacking the cancer by cutting off its nutrient supply lines. In order for this approach to work, it is necessary to understand in detail how angiogenic hormones and growth factors make blood vessels grow.

Several hormones or growth factors have been identified that can make new blood vessels grow. One in particular, termed VEGF (for vascular endothelial growth factor) is highly abundant in many human cancers. Many lung cancers, for example, produce large amounts of VEGF. VEGF is likely to be an important direct stimulator of cancer growth because when VEGF is rendered inactive (in animal models of cancer growth), tumor blood vessel growth is inhibited and tumor growth is blocked. Understanding precisely how VEGF makes blood vessels grow is of great importance because it may lead to new therapies for treating tobacco-related diseases, either by inhibiting angiogenesis, as in lung cancer, or by stimulating angiogenesis, as in coronary artery disease where blood flow to the heart is inadequate.

VEGF initiates the process of new blood vessel growth by binding to the cells lining blood vessels, called endothelial cells. VEGF binds to two specific receptor proteins found only on the surface of endothelial cells. The binding of VEGF turns on the receptors, which then generate signals inside the cell leading ultimately to new blood vessel growth. Understanding the function of these two VEGF receptors and the signals they produce has been challenging. It is not clear whether the two receptors have the same or different functions, or whether they work independently or together.

Our objective is to understand in molecular detail how the two VEGF receptors function to stimulate new blood vessel growth. To do this we will: (1) grow blood vessel cells in culture; (2) establish a method for selectively turning on one receptor, the other receptor, or both receptors simultaneously; (3) identify the signals produced by each receptor inside the cell when the receptor is turned on; and (4) examine how the cells respond to each or both receptors being turned on, in terms of growth, invasion, migration and other cellular responses that occur during angiogenesis. We will then make specific mutations in the receptors to determine in finer detail how the receptors generate the signals that make new blood vessels grow.

This work will define how VEGF, a key regulator of new blood vessel growth both in cancers and in coronary artery disease, works through its receptors to stimulate angiogenesis. This information will be very useful for the design of new therapies for these tobacco-related diseases.