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Believing in Hope:

U-M researchers work to shed light on the grim world of pancreatic cancer, con't.

Diane Simeone
photo credit: Austin Thomason, Michigan Photography

As the tumor grows, symptoms of pain and jaundice become severe enough to send someone to the doctor. But by then, the tumor is often too advanced to be removed with surgery, because it may have grown into or around major arteries and veins or has already spread to the liver, intestines and other organs. Intense chemotherapy combined with radiation can shrink the tumor, but it often grows back.

Many types of cancer develop resistance to chemotherapeutic drugs over time, but pancreatic cancer seems to be inherently resistant and emerges unscathed from chemotherapy and radiation that can eradicate other solid tumors.

"If you look at pancreatic cancer under a microscope, it's a sea of scar tissue with nests of cancer cells," says Simeone. The dense fibrotic tissue surrounding the tumor makes it harder for drugs and radiation to reach and treat the cancer cells and explains some of pancreatic cancer's resistance to treatment.

But there's something else about pancreatic cancer that makes it so deadly an innate aggressiveness that comes from the genetic mutations that drive its development and growth.

"I look at the tumor as a miniature natural selection process," explains Pasca di Magliano. "It accumulates mutations randomly, but if one clone of tumor can grow faster, it will take over. The tumor selects for the meanest cells the ones that ignore all the signals saying you really shouldnt divide anymore."

Scientists like Pasca di Magliano who study the genetics of pancreatic cancer focus on KRAS, because a mutant form of this gene is present in 90 to 95% of all human pancreatic tumors. The cancer-causing KRAS mutant triggers chronic inflammation in the pancreas, according to Pasca di Magliano's newest research. Instead of recruiting immune cells that promote healing, the gene recruits immune cells that inflame surrounding tissue and help the tumor to grow.

Although the KRAS mutation is extremely important, Pasca di Magliano points out that many people acquire this mutation as they age, but never develop pancreatic cancer."You need to have the KRAS mutant and then something else has to happen," she says. The "something else" could be a mutation in a major tumor suppressor gene called p53; abnormal expression of a gene called ATDC, an oncogene discovered in Simeone's lab that is a critical trigger to promote invasiveness; or defects in a signaling pathway called Hedgehog. All of these genetic abnormalities are common in pancreatic cancer.

In fact, researchers have found that malignant pancreatic tumors have an average of 63 mutations, and the specific combination of mutations varies widely from patient to patient. So drugs that target just one mutation may not be the answer.

Simeone believes an important clue to eradicating pancreatic cancer could involve targeting a subset of cells called cancer stem cells, which recently have been found to be present in several types of cancer. In 2007, Simeone and other U-M researchers discovered pancreatic cancer stem cells in human tumors by looking for three specific proteins on the cell's surface. She found that it took just 100 of these stem cells to trigger cancer in research mice, as opposed to thousands of regular tumor cells.

"All our data supports the concept that this cell population is a driver of pancreatic cancer and is particularly resistant to standard therapies," Simeone says. "If we want to cure pancreatic cancer, this cell population needs to be accounted for."

In recent research, Simeone discovered that all pancreatic cancer stem cells are not created equal. She found that cancer stem cells in some human tumors have a different surface protein called c-Met. In combination with another cancer stem cell marker called CD44, c-Met triggers a super-aggressive form of pancreatic cancer that grows and metastasizes rapidly.

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This article first appeared in the Spring, 2012 issue of Medicine at Michigan.