The essential element zinc has been shown in a new study to be a likely tumor suppressor in the most common form of pancreatic cancer, University of Maryland scientists report in the current issue of the journal Cancer Biology & Therapy.
"The report establishes for the first time, with direct measurements in human pancreatic tissue, that the level of zinc is markedly lower in pancreatic adenocarcinoma cells as compared with normal pancreas cells," concludes lead author Leslie Costello, PhD, (at right) professor, Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry (SOD).
The researchers detected a decrease in zinc in cells at the beginning stages and at the advancing stages of cancer.
"The fundamental implication is that we now know something about the development of pancreatic cancer that was not previously known," continues Costello. "It provides a potential approach to treatment, that is, to find a way to get zinc back into the malignant cells, which will kill them," he said.
The scientists further uncovered an important genetic factor that may eventually play into developing an early diagnostic tool. Malignant cells shut down a zinc transporting molecule called ZIP3, which is responsible for guiding zinc through the cell membrane and into the cells. In essence, the researchers have discovered an early genetic/metabolic change in the development of pancreatic cancer. Cancer researchers previously did not know that the ZIP3 gene expression is lost in malignant pancreatic cells, resulting in lower zinc.
Pancreatic cancer is the fourth leading cause of cancer death in the United States, according to the National Cancer Institute (NCI). There are about 42,000 new cases annually in the United States, of which the NCI estimates 35,000 will die.
Patients with pancreatic cancer are usually diagnosed at an advanced stage of the disease because pancreatic cancer often spreads before symptoms develop. Current treatments may extend survival slightly or relieve symptoms in some patients, but they rarely produce a cure.
Pancreatic adenocarcinoma accounts for the vast majority of pancreatic cancer cases. Tumors arise from epithelial cells that line pancreatic ducts.
Costello and Renty Franklin, PhD, professor at the School, have collaborated for many years at the forefront of zinc relationships with prostate cancer, which led them to the more recent studies of pancreatic cancer. The collaborators initiated the current study in late 2009 because substantial evidence had emerged that zinc may be a tumor suppressor in the development and progression of some cancers.
"We wondered why malignant cells show a lost ability to take up zinc," said Franklin. "Certain levels of zinc are toxic to the malignant cell." The researchers say their work implies that it may be possible to develop a chemotherapeutic agent for pancreatic cancer that will get zinc back into and kill the malignant cells.
The pancreas is a vital organ that produces digestive enzymes that go into the intestine and help digest proteins. Early diagnosis of cancer in the pancreas has been difficult because of a lack of information on the factors involved in the development of pancreatic cancer.
The newly discovered involvement of the changes in the ZIP3 gene expression may help identify early states and pre-malignant stages. "The fact that we see the loss of the zinc transporter and a decrease in zinc in the early stages of the cancer indicates that those changes occur even before the cancer is evident. The genetic changes and the changes in zinc levels occur before the pathologist will see any changes in cells under the microscope. That is the kind of early biomarker that people need for cancers," said Costello.
The study team plans more studies of pancreatic cells at various stages of cancer development and also animal studies before planning clinical trials. Costello explains, "We still need to show that we have a way to get zinc into the malignant cells."
The journal paper, titled "Decreased zinc and down regulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma," represents an inter-institutional study. The study team consists of Bernard Levy, DDS, MSD, director of international operation; Jing Zou, post-doctoral fellow; Franklin and Costello, all of the School of Dentistry; Nader Hanna, MB,BCh, associate professor, University of Maryland School of Medicine; Mohamed Desouki, MD, of the Medical University of South Carolina; and Omar Bagasra, PhD, professor, and Leslie Johnson, MS, senior research technologist, biology department, at the South Carolina Center for Biotechnology, Claflin University, in Orangeburg, SC.