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Pancreatic Cancer Aggressiveness Potentially Linked to Microenvironment Protein Marker

NEW YORK (GenomeWeb) – A team from France and Belgium has identified a potential protein biomarker in tissue surrounding pancreatic cancer tumors that appears to correspond to more aggressive forms of the disease.

As they reported in the Journal of Clinical Investigation Tuesday, the researchers used mass spectrometry to assess stroma and tumor samples from four individuals with pancreatic ductal adenocarcinoma, identifying apparent ties between the annexin A6 (ANXA6) protein in cancer-associated fibroblast cells and aggressiveness of the neighboring tumor.

In particular, their results hint that interactions between pancreatic ductal carcinoma tumors and cancer-associated fibroblast cells surrounding them are bolstered by extracellular vesicles in the tumor microenvironment that contain the ANXA6 protein.

"Taken together, our results revealed that cellular crosstalk and [a] hostile environment lead to profound modifications of [cancer-associated fibroblast] activity and consequently impact on tumor cell abilities, tumor evolution, and patients' fate," senior author Richard Tomasini, a cancer researcher at the French National Institute of Health and Medical Research (INSERM), and his co-authors wrote.

With the average five-year-survival rate for this disease hovering around 6 percent, there is interest in coming up with new strategies to detect pancreatic ductal adenocarcinoma, predict the aggressiveness of the disease, and develop more effective treatment strategies, the researchers said. Reasoning that they might get some clues from the protein composition of these tumors and their microenvironment, they used mass spectrometry to analyze samples that had been microdissected from fresh-frozen tumors coinciding with four pancreatic ductal adenocarcinoma cases.

Their analyses led to 484 differentially expressed proteins in the stromal cells, along with 406 proteins that overlapped between the proteomes of the stromal and pancreatic tumor cells. Almost 1,200 more proteins appeared to be specific to the pancreatic ductal adenocarcinoma cells.

The team considered the predicted functions, pathways, and interactions of proteins in the stromal cells, narrowing in on proteins such as ANXA6 and thrombospondin (TSP1) that are involved with extracellular vesicle-mediated cellular interactions. Through a series of subsequent experiments on human cell lines and mouse models with patient tumor xenografts, the researchers found evidence for enhanced tumor cell survival, migration, and aggressiveness in tumors neighboring cancer-associated fibroblasts containing the ANXA6 complex. On the other hand, pancreatic tumor cell migration and metastasis was apparently muted when ANXA6 levels were dialed down in the cancer-associated fibroblasts.

Indeed, when the researchers assessed ANXA6 in circulating extracellular vesicles from more than 150 individuals — including 108 with pancreatic ductal adenocarcinoma, 14 with benign pancreatic conditions, and 30 healthy controls — they saw enhanced ANXA6 levels in those with pancreatic cancer. And higher tumor stage also coincided with more pronounced ANXA6 levels.

"Altogether, these data demonstrate that increase ANXA6 expression level is associated with shortened survival and that ANXA6 level in circulating [extracellular vesicles] could be used as a diagnostic and a predictive marker in [pancreatic ductal adenocarcinoma]," the authors wrote.