The Genetics of Pancreatic Cancer
-- The Discoveries
TGF-ß Receptor and Activin Receptor Mutations
What does TGF-ß do? TGF-ß is a protein that is made and released by cells, so it is present in all tissues and even in blood. Most normal cells stop proliferating when exposed to higher levels of TGF-ß. One of the most remarkable findings about tumor cells from any of a number of sites in the body is that the majority of them do not become suppressed by TGF-ß. When we study the problems of the TGF-ß system in cancers, we are trying to understand one of the most basic abnormalities of cancers, which is their inability to respond to the body's own normal signals which should control their growth. Perhaps by finding a way to restore these TGF-ß signals, we can re-establish a natural and powerful means to rein in the tragic aggressiveness of cancer.
Why are TGF-ß receptors important? Cells have receptors on their surface that are specially made to send signals through the cell when the cell comes in contact with certain kinds of molecules. TGF-ß receptors have this role. They send signals through certain pathways in the cell. One of the most important pathways includes the protein Dpc4, which is often mutated in pancreatic cancer. Mutations or deletions of the TGF-ß receptors is thus another way that cancer cells become resistant to the normal growth controls that operate in the body. There are two types of TGF-ß receptor, called the type I receptor and the type II receptor. About 2% of pancreatic cancer have mutations of each receptor type. We were the first to find mutations of the type II receptor in pancreatic cancer, and the first to find genetic inactivation of the type II receptor in any cancer type.
What about activin? There are other proteins similar to TGF-ß, and these other proteins need their own receptor system as well. One of these is called activin. Not much is known about activin in cancers, but it appears to suppress cell growth just as TGF-ß does. Most of the attention, however, had focused on TGF-ß. We decided to take a look at the activin system, and were the first to find mutations of the activin type 1B receptor in human cancer. About 2% of pancreas cancers have genetic inactivation of the activin type 1B receptor, which would be expected to prevent activin from serving its role to control the number of cancer cells.