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Cell Surface Heparan Sulfate Proteoglycan for the Earlier Diagnosis of Pancreatic Cancer

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 (ductal adenocarcinoma of the pancreas). 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 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.

[More Here]

Dale O’Brien, MD

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