Cell Surface Heparan Sulfate Proteoglycan Found on Extracellular Vesicles in Serum May Aid in the Earlier Diagnosis of Cancer of the Pancreas
Yesterday, European researchers and those from MD Anderson Cancer Center/ University of Texas in Houston published an article in the prestigious journal, Nature, which carries the possibility of being a game-changer in the earlier diagnosis and consequent treatment of pancreatic cancer. It is difficult to overstate the potential for significant positive effects of these findings in the treatment of pancreatic cancer should the fascinating results bear up under replication and scrutiny.
The results of the presented research identify a diagnostic marker for pancreatic cancer (ductal adenocarcinoma of the pancreas) that exists as an exosome containing a specific protein/saccharide complex that is attached to the outside wall of its spherical structure as it courses its way through human fluids (including serum) in humans with pancreatic cancer. This proteoglycan marker is known as glypican-1, a cell surface heparan sulfate.
The presence of these “glypican-1 exosomes” in human serum demonstrated 100% sensitivity and 100% specificity as to the presence of pancreatic cancer in individuals. These remarkable findings were seen in late and early pancreatic cancer, and extended even to the putative precursor: intraductal papillary mucinous neoplasms (IPMNs).
Here at our Pancreatica blog we have been intrigued by “exosomes” in the interest of the earlier diagnosis of pancreatic cancer for a while [Here] and [Here]. Exosomes, first discovered in the 1980s, are round lipid structures containing intracellular bits of RNA, DNA, parts of cellular proteins, and other substances. In a process that is not fully understood (and which may not be uniform) exosomes appear to be formed by the pinching off or budding of a cell wall. The resultant small structure has a typical diameter of approximately 30 to 100 nanometers, and essentially “floats” through the fluids of the mammalian body. Exosomes are found essentially in all fluids including, for example, saliva. It has been thought that the function of exosomes may include extracellular communication, waste disposal, unknown immune response or interaction, and tumor invasion. An exosome appears to be able to transfer its contents from one cell to another, even at a distance.
The fifteen named authors of this study are researchers from medical institutions in Dresden, Germany; Porto, Portugal; Orviedo, Spain; Madrid, Spain; and Houston, Texas. The corresponding author is Raghu Kalluri, MD, PhD at the Department of Cancer Biology, Metastasis Research Center, University of Texas/ MD Anderson Cancer Center, Houston, Texas 77054, USA. The 29-page article was published on June 24, 2015 in the journal Nature.
The research was done with cell lines, mice, and in human subjects. Other findings of this work demonstrate that the level of the concentration of the glypican-1 exosomes is correlated with overall pancreatic cancer tumor burden, and with the survival duration of pre-operative and post-operative patients. Glypican-1 exosomes reliably demonstrate KRAS mutation (common in pancreatic cancer, and thought to be an oncogenic driver) in messenger-RNA found in the structures. Glypican-1 exosomes appear to be a more valid biomarker than CA 19-9 for the detection of pancreatic cancer. In genetically-engineered mice models, glypican-1 exosomes are detectable in serum before pancreatic cancer tumors show anatomically by MRI. If the findings hold, the increased specificity of the glypican-1 exosomes avoids the pitfalls of confusion with pancreatitis or other pancreatic disorders, as is now the case with a number of biomarkers including CA 19-9.
The researchers additionally found increased glypican-1 exosome levels (but not as definitive) in breast cancer. And they note that glypican-1 could serve as a pan-specific marker of cancer exosomes.
The pancreas related patients and healthy controls were all from Germany: the University Hospital of Heidelberg and the University Hospital of Dresden. These included 246 patients with pancreatic cancer (pancreatic ductal adenocarcinoma), 24 patients with pancreatitis, 8 patients with a benign serous cystadenoma, 5 patients with diagnosed IPMN, and 20 healthy controls. The University of Texas / MD Anderson Cancer Center contributed data from 32 women with breast cancer.
In passing, we note that heparan sulfate is a member of the glycosaminoglycan family of carbohydrates and is very closely related in structure to heparin, the anticoagulant in common use. Both consist of a variably sulfated repeating disaccharide unit.
These research findings are remarkable. If replicable and verified, they will be a major breakthrough for the early diagnosis of pancreatic cancer. This could lead to potentially curative surgery for a major portion of those found to have pancreatic cancer, which now is available only to about 15% of patients upon diagnosis. We eagerly await confirmation.
Dale O’Brien, MD
In a certain way, the initial treatment considerations for local and advanced pancreatic cancer are not as complex as those of locally advanced adenocarcinoma of the pancreas. Local cancer is typically treated with surgical resection – some version of the Whipple Procedure. And the treatment of advanced pancreatic cancer is generally some form of chemotherapy regimen. The “standard” for non-operable locally advanced pancreatic cancer has been chemoradiation. And an active area of inquiry has been the best treatment option for borderline resectable locally advanced pancreatic cancer, or perhaps unresectable locally advanced pancreatic cancer as based on vascular encasement or abutment by the tumor.
Now comes a study by Allendorf and his surgical colleagues from Columbia University in New York City that examines outcomes for over five hundred patients who received the pancreaticoduodenectomy (Whipple) surgery for locally advanced pancreatic cancer at Columbia from the years 1992 to 2011. The authors’ review of patient records treated at their institution initially found 643 patients with locally advanced disease who had appeared to fit surgical criteria. At surgery, only 506 of these patients were found by the operating surgeon to merit surgery. Published in the May 2014 edition of the World Journal of Surgery, the authors looked at survival duration in terms of neoadjuvant status as well as whether vascular resection was done.
The authors found that although neoadjuvant therapy appeared associated with an increase in operative mortality (7% vs. 3%), that more neoadjuvant pancreatic cancer patients underwent vascular resection, and that neoadjuvant therapy status significantly increased overall survival (as compared to no receipt of neoadjuvant treatment) at a p < 0.5 confidence level of 27.3months versus 19.7 months.
It tentatively appears that certain patients with apparently unresectable locally advanced pancreatic cancer – as determined by traditional criteria – may gain a potentially improved survival advantage if they respond to neoadjuvant therapy such that they then become candidates for pancreatic surgery, including vascular resection.
This is an interesting and fine study that on one hand further complicates the treatment landscape for locally advanced pancreatic cancer, but offers potential improved results for many.
Dale O’Brien, MD
Our non-profit organization has been honored as the beneficiary of an incredible effort made by eleven 8th graders on a mission to help support pancreatic cancer.
With the support of friends, family, teachers, coaches and neighbors they put on a 5K Fun Run Event. These extraordinary young members of the National Junior Honor Society at Harrison Middle School have shown astounding dedication to help a very serious cause. We sincerely thank them and their community for such a generous exhibition of human kindness.
We are very impressed by their social effort, humbled by this effort, and grateful to these young men and women – and to the efforts of their families and community. Thank you guys !