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Understanding Pancreatic Cancer

Three studies shed light on the science behind the development and behavior of this disease

Claiming some 34,000 lives a year, pancreatic cancer is the fourth-leading cause of cancer death in the United States. The disease frequently is detected after it has spread, and only 4 percent of individuals with pancreatic cancer live for five years after diagnosis.

The Jefferson Center for Pancreatic, Biliary and Related Cancers is leading the fight against pancreatic cancer. In addition to performing the highest volume of pancreatic surgeries of any center in the tri-state area, this team also actively explores the basic science behind the development and behavior of the disease.

In recent months, the team has announced the findings of three significant studies led by Hwyda Arafat, MD, PhD, associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University. The work of Dr. Arafat and her colleagues reinforces the advantages of seeking treatment at Jefferson.

Study #1: Traditional herbal medicine kills pancreatic cancer cells

An herb used in traditional medicine by many Middle Eastern countries may help in the fight against pancreatic cancer, one of the most difficult cancers to treat. Researchers at the Kimmel Cancer at Jefferson have found that thymoquinone – an extract of nigella sativa seed oil – blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.  

While the studies are in the early stages, the findings suggest that thymoquinone could eventually have some use as a preventative strategy in patients who have gone through surgery and chemotherapy or in individuals who are at a high risk of developing cancer.

According to Dr. Arafat, nigella sativa helps treat a broad array of diseases, including some immune and inflammatory disorders. Previous studies also have shown anti-cancer activity in prostate and colon cancers, as well as antioxidant and anti-inflammatory effects.

 

Study #2: Blood pressure drugs halt cell growth

Researchers at the Kimmel Cancer Center at Jefferson are inching closer to understanding how common blood pressure medications might help prevent the spread of pancreatic cancer. They have found in the laboratory that one type of pressure-lowering drug called an angiotensin receptor blocker inhibits pancreatic cancer cell growth and causes cell death.

In earlier work in the laboratory, Dr. Arafat and her team showed that angiotensin receptor blockers may help reduce the development of tumor-feeding blood vessels, a process called angiogenesis. Other studies have linked a lower incidence of cancer with the use of angiotensin blocking therapies. Such drugs, she says, may become part of a novel strategy to control the growth and spread of cancer.

One of these drugs – AT1R (Ang II type 1 receptor) blockers – inhibits the function of the hormone angiotensin II (Ang II) in the pancreas. The receptor is expressed in pancreatic cancer cells. Ang II increases the production of VEGF, a vascular factor that promotes blood vessel growth in a number of cancers. High VEGF levels have been correlated with poor cancer prognosis and early recurrence after surgery. Dr. Arafat’s research team has shown that Ang II indirectly causes VEGF expression by increasing AT1R expression.

Dr. Arafat’s group explored the effects of blocking AT1R on the pancreatic cancer cell reproductive cycle and programmed cell death, or apoptosis, and the mechanisms involved. It found that blocking AT1R inhibited pancreatic cancer cell growth and promoted cell death.

“This happens through inducing the activity of the gene p53, which controls programmed cell death, and also by inhibiting anti-cell death pathways such as those involving the gene bcl-2,” she explains. The team reported its findings in April at the annual meeting of the American Association for Cancer Research in San Diego.

The researchers also found that blocking AT1R affects p21, a gene that regulates the cell cycle.

“We found that blocking this receptor can cause cell cycle arrest,” she notes. “This is really exciting because the role of this receptor has never been known. It’s never been connected to cell division or apoptosis. We’re also now further exploring the mechanisms involved. The exciting thing is that this receptor already has so many available pharmaceutical blockers on the market.” Ultimately, the group hopes to be able to test these agents in human trials, she says.

Study #3: Discovery may help explain link between smoking and pancreatic cancer

Researchers at the Kimmel Cancer Center at Jefferson have preliminary evidence indicating one possible reason why cigarette smokers are at higher risk for pancreatic cancer. Data presented in April shows that they have found that nicotine in cigarettes increases the production of a protein that is known to promote cancer cell survival, invasion and spread.

According to Dr. Arafat, the protein, osteopontin, is found in a variety of fluids in the body, such as plasma, cerebrospinal fluid, synovial fluid and breast milk. Osteopontin is also present in different organs and plays an important role during embryonic development. Recent studies have demonstrated that osteopontin levels are significantly higher in the blood and pancreas tissue of pancreatic cancer patients. When over-produced, the protein can make cancer cells more likely to become metastatic.

Dr. Arafat wanted to see if osteopontin might play a role in the cigarette smoking-pancreatic cancer connection. In collaboration with groups at the University of Nebraska and Rutgers University, Dr. Arafat and her co-workers looked at rats exposed to cigarette smoke and measured the amount of osteopontin in the rat pancreas and blood. They found that the more cigarette smoke to which the rats were exposed, the greater the amount of nicotine in the blood and osteopontin in the pancreas.

The researchers also looked at osteopontin expression in pancreatic cancer cell lines exposed to nicotine, finding that osteopontin expression went up when the cells were exposed to more nicotine.

“We found that dose-dependently, nicotine increased osteopontin expression not only through transcriptional but also translational (protein secretion) levels in pancreatic cancer cells,” Dr. Arafat explains. Pancreas tissue samples from pancreatic cancer patients also showed higher-than-normal levels of the protein.

Dr. Arafat believes that osteopontin could be a drug target: “We are now proposing that perhaps blocking osteopontin can interfere with the progression of pancreatic cancer and other cancers,” she says, adding that her team would like to understand more about osteopontin’s effects on pancreatic cancer cell behavior. Dr. Arafat’s group now is comparing differences in osteopontin expression between smokers and non-smokers.

“For example, if you put the cells with nicotine and block osteopontin, will the cells still be migratory? Is it osteopontin or something else in combination that is at work here?” she asks.

For more information

For more information about the Jefferson Center for Pancreatic, Biliary and Related Cancers, visit the Center’s website. Make an appointment with a Jefferson physician online or by calling 1-800-JEFF-NOW.