Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. The development of molecular markers and imaging probes for incipient PDAC would enable earlier detection and guide the development of interventive therapies. Here we sought to identify novel molecular markers and to test their potential as targeted imaging agents.
Methods and Findings
Here, a phage display approach was used in a mouse model of PDAC to screen for peptides that specifically bind to cell surface antigens on PDAC cells. These screens yielded a motif that distinguishes PDAC cells from normal pancreatic duct cells in vitro, which, upon proteomics analysis, identified plectin-1 as a novel biomarker of PDAC. To assess their utility for in vivo imaging, the plectin-1 targeted peptides (PTP) were conjugated to magnetofluorescent nanoparticles. In conjunction with intravital confocal microscopy and MRI, these nanoparticles enabled detection of small PDAC and precursor lesions in engineered mouse models.
Our approach exploited a well-defined model of PDAC, enabling rapid identification and validation of PTP. The developed specific imaging probe, along with the discovery of plectin-1 as a novel biomarker, may have clinical utility in the diagnosis and management of PDAC in humans.
Kimberly Kelly and colleagues describe the discovery of plectin-1 as a novel biomarker for pancreatic ductal adenocarcinoma and the subsequent development of a specific imaging probe using this marker.
Pancreatic cancer is a leading cause of cancer-related death in the US. Like all cancers, it occurs when cells begin to grow uncontrollably and to move around the body (metastasize) because of changes (mutations) in their genes. If pancreatic cancer is found early, surgical removal of the tumor can sometimes provide a cure. Unfortunately, this cancer rarely causes any symptoms in its early stages and the symptoms it does eventually cause—jaundice, abdominal and back pain, and weight loss—are also seen in other illnesses. In addition, even though magnetic resonance imaging (MRI) or other noninvasive imaging techniques can be used to look at the pancreas, by the time tumors are large enough to show up on MRI scans, they have often already spread. Consequently, in most patients, pancreatic cancer is advanced by the time a diagnosis is made, hence surgery is no longer useful. These patients are given radiotherapy and chemotherapy but these treatments are rarely curative and most patients die within a year of diagnosis.
Why Was This Study Done?
If more pancreatic cancers could be found before they had metastasized, it should extend the life expectancy of patients with this type of cancer. An early detection method would be particularly useful for monitoring people at high risk of developing pancreatic cancer. These include people with certain inherited cancer syndromes, pancreatitis (inflammation of the pancreas), and diabetes. Because cancer cells have many mutations, they express different proteins on their cell surface from normal cells. If these proteins could be identified, it might be possible to develop an “imaging probe”—a molecule that binds to a protein found only on cancer cells and that can be detected with MRI, for example—for early detection of pancreatic cancer. In this study, the researchers use a technique called “phage display” to identify several peptides (short sequences of amino acids, the constituent parts of proteins) that specifically bind to pancreatic cancer cells early in their development. They then investigate the possibility of developing an imaging probe from one of these peptides.
What Did the Researchers Do and Find?
The researchers isolated early pancreatic cancer cells from a mouse model of human pancreatic ductal adenocarcinoma (PDAC; the commonest type of pancreatic cancer). Then, by mixing together these cells and normal mouse pancreatic cells with a library of phage clones (phages are viruses that infect bacteria; a clone is a group of genetically identical organisms), each engineered in the laboratory to express a random seven amino-acid peptide, they identified one clone, clone 27, that bound to the mouse tumor cells but not to normal cells. Clone 27 also showed up in the cancer cells in samples of mouse pancreatic intraepithelial neoplasias (PanINs; precursors to pancreatic cancer), mouse PDACs, and human PDACs.
The peptide in clone 27, the researchers report, binds to plectin-1, a protein present both inside and on the membrane of human and mouse PDAC cells but only on the inside of normal pancreatic cells. Finally, the researchers attached this plectin-1–targeted peptide (PTP) to a nanoparticles that was both magnetic and fluorescent (PTP-NP) and used special microscopy (which detects the fluorescent part of this very small particle) and MRI (which detects its magnetic portion) to show that this potential imaging probe was found in areas of PDAC (but not in normal pancreatic tissue) in the mouse model of human PDAC.
What Do These Findings Mean?
These findings identify PTP as a peptide that can distinguish normal pancreatic cells from pancreatic cancer cells. The discovery that plectin-1 (a cytoskeletal component) is abnormally expressed on the cell surface of PDACs provides new information about the development of pancreatic cancer that could eventually lead to new ways to treat this disease. These findings also show that PTP can be used to generate a nanoparticle-based imaging agent that can detect PDAC within a normal pancreas. These results need to be confirmed in people—results obtained in mouse models do not always reflect what happens in people. Nevertheless, they suggest that PTP-NPs might allow the noninvasive detection of early tumors in people at high risk of developing pancreatic cancer, an advance that could extend their lives by identifying tumors earlier, when they can be removed surgically.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050085.
• The Panreatic Cancer Action Network and the Lustgarten Foundation for Pancreatic Cancer Research provide information, support, and advocacy for patients, families, and healthcare professionals
• The MedlinePlus Encyclopedia has a page on pancreatic cancer (in English and Spanish). Links to further information are provided by MedlinePlus
• The US National Cancer Institute has information about pancreatic cancer for patients and health professionals (in English and Spanish)
• The UK charity Cancerbackup also provides information for patients about pancreatic cancer