This is the first time the mechanism of Thrombospondin-1 (TSP1) regulation has been demonstrated genetically in laboratory animals with cancer, said molecular biologist Luisa Iruela-Arispe, a researcher at UCLA’s Jonsson Cancer Center and an assistant professor in the UCLA Department of Molecular, Cell and Developmental Biology.
Iruela-Arispe’s research was outlined in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences. The article can be found at http://www.pnas.org/.
The UCLA discovery, the result of five years of laboratory experimentation and genetic analysis, could lead to new treatments targeted to fight malignancies, Iruela-Arispe said.
Human beings can live, and most do, with microscopic cancers in their bodies. It’s when these cancers grow and spread that they create havoc. A solid tumor cannot grow beyond the size of a pinhead unless it has an independent blood supply to deliver the oxygen and nutrients it needs to advance and spread. In order to grow and invade, a tumor develops its own blood supply through a process called angiogenesis. Researchers have long theorized that angiogenesis-inhibiting drugs could interrupt that process, cutting off the blood supply to the tumor and, it is hoped, killing it.
Already several angiogenesis inhibitors tested in clinical trials have been shown to suppress tumor growth, but their mechanism of action is often unclear. In the case of TSP1, recognized more than a decade ago as the first naturally occurring protein to act as an angiogenesis inhibitor, Iruela-Arispe and her team of researchers set out to discover the mechanism used to regulate angiogenesis.
"As human beings, we have many internal controls in place to prevent tumors from growing and expanding. These are our gatekeepers," Iruela-Arispe said. "We all have cancers that occur within us, but the body throws up a lot of obstacles to keep the cancers from growing. TSP1 is likely to be one of those obstacles, and we were able to prove that it does regulate angiogenesis and tumor growth through a novel mechanism."
To uncover the mechanism, Iruela-Arispe and her team studied a strain of laboratory mice with breast cancer that overexpressed — or had higher than normal levels of — TSP1. The mice that overexpressed TSP1 developed much smaller tumors that took longer to grow than a strain of mice that expressed no TSP1 at all. Of the mice that overexpressed TSP1, 20 percent appeared to be protected from cancer because although they carried the genetic mutation for the disease, the mice did not develop any tumors at all, Iruela-Arispe said.
The strain of mice with no TSP1, on the other hand, developed very large tumors very quickly. Iruela-Arispe said 100 percent of these mice developed breast cancer. Additionally, the blood supply created by the tumors in the mice with no TSP1 was better developed and more efficient than the blood supply in the mice that overexpressed TSP1. The capillaries in the mice lacking TSP1 were larger in diameter and more frequent in number, Iruela-Arispe said.
Iruela-Arispe’s research shows that TSP1 regulates the activation of a molecule called MMP9, which in previous research has been shown to promote angiogenesis and allow tumors to spread more easily to other organs. Iruela-Arispe’s data indicates that TSP1 could be suppressing the activation of MMP9, providing protection from tumor growth.
This discovery could be used to develop drugs that mimic TSP1, perhaps preventing tumors from developing independent blood supplies. In effect, the drugs would starve the tumors of nutrients and oxygen, possibly killing them.
"We know a lot about what promotes angiogenesis," Iruela-Arispe said. "Unfortunately, we know very little about what regulates it."
Iruela-Arispe has been studying TSP1 for nearly a dozen years. Her scientific team will continue to study the protein, "to build on this discovery and see if we can learn more about it and how it may help protect us from developing cancer," she said.
For more information about UCLA’s Jonsson Cancer Center, its people and resources, visit our Web site at http://www.cancer.mednet.ucla.edu/.
Journal
Proceedings of the National Academy of Sciences