(SALT LAKE CITY)—Cancer of the pancreas is usually not detected until it's too late to cure. But precursor lesions that form in the pancreas and its ducts can signal the disease before it strikes, 如果发现得够早的话, they can be prevented from progressing to become cancer.
在一项新的研究中, researchers led by a molecular biologist at the University of California, 旧金山（UCSF）, report two breakthroughs in understanding those lesions and their role in pancreatic cancer: the development of the first mouse model that simulates a precursor lesion called intraductal papillary mucinous neoplasia (IPMN), and the identification of an enzyme, 缺失, that appears to help cause the formation of IPMN lesions while also suppressing another precursor lesion.
A University of Utah co-author on the study says the research proves that epigenetics – changes in genetic activity caused by forces other than modifications in the DNA sequence, such as when genes are turned on or off – play a role in pancreatic ductal adenocarcinoma (PDA), the most common type of cancer of the pancreas. "These findings may provide an avenue for intervention in PDA, if we can understand the epigenetics,” 马修一个. Firpo, Ph值.D., research associate professor of 手术.
Mathias Hebrok博士.D., of UCSF School of Medicine, led the study published on Sunday, Feb. 23, 2014, in 自然细胞生物学. 肖恩·J. Mulvihill, M.D., University of Utah professor of 手术, associate vice president for clinical affairs and CEO of the University of Utah Medical Group, is also a co-author on the paper. He and Firpo have banked human samples of IPMN for many years and shared some with Hebrok for his research.
"This study not only represents a longstanding collaboration between the University of Utah and UCSF but also is a reflection of the transition in research from single investigators working on their own to highly collaborative studies with experts in many fields from different institutions,马尔维希尔说, who is also a pancreatic cancer surgeon and an investigator with the University of Utah's 亨茨曼癌症研究所.
With a five-year survival rate of just 4.4 percent, cancer of the pancreas is the fourth leading cause of cancer deaths. In 82 percent of cases, the disease is found when it's too late to remove the tumor. Tumors that are smaller than 2 centimeters and haven't metastasized are considered the best cases for 手术. When tumors are operable, the five-year survival rate approaches 40 percent, according to Firpo.
IPMN is one of three classes of pancreatic cancer precursor lesions. Pancreatic Intraepithelial Neoplasia (PanIN) and mucinous cystic neoplasm (MCN) also are lesions that precede pancreatic cancer. PanINs are the lesions most commonly thought to lead to PDA.
缺失 is an enzyme that regulates gene expression by altering DNA structure in the nucleus of a cell, a process known as chromatin remodeling. Hebrok found that when the 缺失 gene is knocked out in mice that are predisposed to PanIN development and subsequent PDA, lesions form that are similar to human IPMN. He confirmed that through the human IPMN samples from Mulvihill and Firpo.
But in addition to 缺失's role in forming IPMN lesions, Hebrok discovered that when the gene is knocked out in mice that have an activated gene called KRAS, whose role is to help regulate cell division, PanIN lesions occur less frequently. This indicates that 缺失 protects against PanIns but also helps cause IPMN lesions.
"As someone who researches pancreatic cancer, I think this discovery is significant because it defines mechanisms that lead to this cancer in ways that we didn't know about before,菲尔波说。, who's also a member of the Pancreas Cancer 研究 Program and Experimental Therapeutics Program at the University of Utah's 亨茨曼癌症研究所. "It illuminates an area that were just guessing at before."
It's also significant because people with IPMN, which has been more frequently diagnosed in recent years, have a much better prognosis for survival than those with PanINs. The symptoms of IPMN usually become noticeable before cancer develops, meaning the lesions can be treated before a cancerous tumor forms. PanINs, however, typically don't show symptoms before an inoperable tumor has formed.
That's why it is so important to find the disease as early as possible, according to Mulvihill. "Better understanding of the beginnings of pancreatic cancer gives us much more hope for both prevention and cure."