TGF-a: we need it, but too much is bad
Abstracts
Initial Award Abstract |
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We plan to study how a protein, known as transforming growth factor-alpha (TGF-alpha), contributes to the development of up to 85% of lung cancers (a disease mainly caused by smoking of cigarettes). TGF-alpha is present in both normal and cancer cells and can stimulate cell growth. However, there is a difference in the amount of TGF-alpha produced in normal and cancer cells. The human body is a terrific machine in which every part is built according to what it is used for. Therefore, only a limited level of growth is needed for most cells in the body. Thus, normal cells are allowed to produce only a small amount of TGF-alpha. When cells in the body have lost their ability to control their growth, they may form cancers. Many cancer cells, including most lung cancer cells, produce much more TGF-alpha than normal cells.
Not only do normal and cancer cells produce different amounts of TGF-alpha, they also use it differently. In normal tissues, TGF-alpha is retained by the producer cells, therefore it only stimulates the producer cells themselves or the neighboring cells right next to the producer. However, cancer cells release TGF-alpha into the environment made of tissue fluid. As a result, the freely diffusible TGF-alpha can stimulate the growth of cells at great distance from the producer cells. The overproduction of TGF-alpha by cancer cells helps cancers grow and spread from their original site to other organs. These disseminated cancer cells form secondary tumors which eventually cause malfunction of multiple and important organs at late stage of disease and is the major cause of death of cancer patients.
Release of TGF-alpha apparently is a strategy that cancer cells use to gain growth advantages over normal cells. However, medical researchers know very little about how cancer cells can release TGF-alpha. In this proposed study, we will attempt to address this important question. We hope that our work can identify which protein is responsible for release of the TGF-alpha from producer cells into the environment, and can provide information with respect to what kind of event can control this release. Therefore, our work is important and significant not only because it will help us understand how cancers, including those of the lung, occur and progress, but may also help develop new treatments for cancer patients. |
Final Report |
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We proposed to study how a growth factor called transmembrane growth factor alpha (TGF-a) contributes to the development of cancers that affect 85% of lung cancer patients and are mainly caused by smoking of cigarettes.
TGF-(x is present in both normal and cancer cells, and can stimulate cell growth. In normal tissues, TGF-a is largely retained by the producer cells; therefore it only stimulates the producer cells themselves or the neighboring cells right next to the producer. However, cancer cells using a protease to release TGF-a into the environment made of tissue fluid. As a result, the freely diffusible TGF-a can stimulate the growth of cells at appreciably distance from the producer cells.
Release of TGF-a is a strategy that cancer cells use to gain growth advantages over normal cells. However, medical researchers know very little about how cancer cells can release TGF-a. I have been investigating how the protease that releases TGF-a becomes active in cancer cells, and identified several critical regulators of the protease activity. My studies show that these regulators are proteins that essentially function as signaling transducers that determine how cells should operate, and that become hyperactive in response to cancer causing agents. The generation of free TGF-a serves to enhance further the growth of cancer cells that already grow faster than normal cells. Excessive amount of free TGF-a generated can also cause dissemination of cancer cells to form secondary tumors. Our work not only is leading us to a better understanding of cancer progression, but also contributes to the development of new therapeutic strategies for cancer treatment since inhibition of the signaling transducers and the protease can prevent TGF-a release and stop the growth of cancer cells. |
Publications
| Ectodomain shedding of TGF-a and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinate signaling cascades |
| Periodical: Embo Journal |
Index Medicus: |
| Authors: Fan H, Derynck R |
ART |
| Yr: 1999 |
Vol: 18 |
Nbr: |
Abs: |
Pg: 6962-6972 |
| Ectodomain shedding of TGF-a and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinate signaling cascades |
| Periodical: Embo Journal |
Index Medicus: |
| Authors: Fan H, Derynck R |
ART |
| Yr: 1999 |
Vol: 18 |
Nbr: |
Abs: |
Pg: 6962-6972 |
