Researchers have developed an assay that identifies patients with late-stage pancreatic cancer with 100% accuracy. It also distinguishes people with precancerous pancreatic lesions from those with benign pancreatic diseases or healthy individuals.
Exosomes are lipid bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids, and circulate in the blood. In the June 25 issue of Nature, Sonia A. Melo et al describe the isolation and detection of pancreatic cell-derived exosomes from the circulation of patients.
Using mass spectrometry analyses, they found that levels of a cell-surface proteoglycan, glypican-1 (GPC1), were increased on cancer cell-derived exosomes, compared with those from non-cancer cells. These GPC1+ circulating exosomes (crExos) could be measured in serum samples of patients using flow cytometry.
Melo et al analyzed serum samples and tissues from almost 250 patients with pancreatic ductal adenocarcinoma (PDAC), as well as patients with pancreatitis, benign serous cystadenoma, intraductal papillary mucinous neoplasms (IPMNs), or chronic pancreatitis, and healthy donors.
They found the presence of pGPC1+ crExos (but not the pGPC1 protein alone) in serum to distinguish healthy subjects and patients with benign pancreatic disease from patients with early- and late-stage pancreatic cancer with 100% specificity and sensitivity.
The levels of GPC1+ crExos in serum from patients with pancreatic cancer precursor lesions (5 with IPMNs) were consistently higher than the levels of GPC1+crExos in serum from healthy donors, and also higher than in the group with benign pancreatic diseases (18 patients with pancreatitis and 8 with cystic adenomas). Patients with benign pancreatic disease had similar levels of GPC1+ crExos levels (average 2.1% GPC1+ crExos) as healthy donors.
When the authors compared patients with stage I–IV pancreatic cancer to healthy donors and patients with benign pancreatic disease, receiver operating characteristic curve analysis found GPC1+ crExos to be a near-perfect classifier, with an area under the curve value of 1.0, sensitivity and specificity values of 100%, and positive and negative predictive values of 100%.
Interestingly, 75% of patients with breast cancer had higher levels of GPC1+ crExos than healthy donors.
Levels of GPC1+ crExos correlated with tumor burden and survival of patients before and after surgery. The Houston Chronicle wrote that levels of the protein were markedly lower after surgical removal of patients’ tumors. NBC news wrote that levels of GPC1+ crExos might therefore be used to follow the progression of the disease.
Melo et al compared the specificity and sensitivity of GPC1+ crExos to levels of carbohydrate antigen 19-9 (CA19-9; also known as sialyl LewisA)—standard biomarker for patients with PDAC. They found levels of CA19-9 to be increased in the serum of patients with PDAC, compared with healthy donors. However, levels of CA19-9 were also significantly increased in the serum of patients with benign pancreatic disease, and failed to distinguish patients with pancreatic cancer precursor lesions from healthy donors
The authors found that GPC1+ crExos from patients and from mice with spontaneous pancreatic tumors carry specific mutations in KRAS.
GPC1+ crExos identified pancreatic cancer in 16-day-old mice with no histologic features of the cancer and negative findings from magnetic resonance imaging analysis.
Melo et al conclude that assays for GPC1+ crExos could be used to identify and treat patients with early-stages of pancreatic cancer. Pancreatico-duodenectomy can cure patients if tumors are detected early. However, only about 15% of patients currently present with surgically resectable tumors.
In a News and Views article published in the same issue of Nature, Clotilde Thery (Institut Curie, Paris) wrote that although the potential implications of such a test are huge, the findings need to be replicated in much larger groups.
She explained that the novelty of the findings resides in the presence of GPC1 in circulating vesicles in serum, and in their striking value as a biomarker. She says that interestingly, detection of serum GPC1 by ELISA, without its concentration in vesicles, is not a better marker of pancreatic cancer than CA 19-9. Thery says the researchers are the first to show that circulating vesicles in blood can be a source of specific and reliable diagnostic biomarkers for cancer (see figure).
Cancer physician Alan Venook (University of California, San Francisco) told the Los Angeles Times that the numbers tested by the researchers, however, aren’t nearly large enough to draw major conclusions.
“Don’t get me wrong, this is where we start. This is a very cool observation, well worth following. But this is not a biomarker yet,” Venook told the Los Angeles Times.