LAKE TAHOE, Nev. Pancreatic cancer is one of the deadliest forms of cancer, defying most treatments. Its ability to evade therapy may be attributable to the presence of cancer stem cells, a subset of cancer cells present in pancreatic tumors that drive tumor growth by generating bulk tumor cells. Cancer stem cells are notorious for their ability to resist traditional chemotherapies.
However, scientists at the University of California, San Francisco (UCSF), have discovered that two proteins KRAS and leukemia inhibitory factor (LIF) help create cancer stem cells and that the latter can be targeted to block them.
These results were presented at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, held here from June 18-21.
In many different types of tumors, a constitutively active, mutant form of the signaling protein KRAS helps drive the uncontrolled tumor cell proliferation that is a hallmark of cancer. In fact, more than 90 percent of pancreatic cancers exhibit KRAS mutations, but the link between KRAS and cancer stem cells has been tenuous until now.
Using human pancreatic cancer cell lines and mouse fibroblasts and pancreatic cancer cells, Man-Tzu Wang, Ph.D., a postdoctoral researcher in the McCormick lab at the Helen Diller Family Comprehensive Cancer Center at UCSF, and colleagues showed that KRAS causes cells to acquire and maintain stem cell-like properties.
"We know that KRAS is a very potent driver of pancreatic cancer, but we don't know how to drug it," said Wang. "Our results showed we can block KRAS-mediated cancer stem cells by blocking LIF activity."
KRAS is difficult to target therapeutically. Taking the next logical step, the researchers began looking for proteins that function downstream of KRAS in the generation of pancreatic cancer stem cells to determine if any of them could be potential drug targets. They found a number of candidates but focused on LIF, a protein known to regulate stem cell development. Moreover, they found that LIF is "druggable," making it a potential target for treatment.
Using neutralizing antibodies or shRNA, the team knocked down LIF activity or expression and found that each reduced the in vitro stem cell-like properties of mouse pancreatic cancer cells.
"We think our data indicate that blocking LIF can bring a significant improvement to cancer treatment," Wang said.
Knocking down cancer stem cells is critically important. Because these cells are slow-growing, they are often resistant to traditional chemotherapies, which target fast-growing cells. In addition, they also contain mechanisms that pump drugs out of the cell. Their survival allows them to continue to differentiate into mature cancer cells, leading to recurrent tumors.
Though there are no drugs currently available that target LIF, Wang is hopeful that these new data will spur the development of such products and generate new pancreatic cancer therapies.
|Contact: Jeremy Moore|
American Association for Cancer Research