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Pancreatic fibroblasts are continuously gaining ground as an important component of tumor microenvironment that dynamically interact with cancer cells to promote tumor progression. In addition, these tumor-infiltrated fibroblasts can acquire an activated phenotype and produce excessive amounts of extracellular matrix creating a highly dense stroma, a situation known as desmoplasia. Desmoplasia, along with the uncontrolled proliferation of cancer cells, leads to the development of compressive forces within the tumor, generating the so-called solid stress. Solid stress is previously shown to affect cancer cell proliferation and migration, however there is no pertinent study taking into account the effects of solid stress on fibroblasts and whether these effects contribute to tumor progression. In this work, we applied a defined compressive stress on pancreatic fibroblasts, similar in magnitude to that experienced by cells in native pancreatic tumors. Our results suggest that solid stress stimulates fibroblasts activation and strongly upregulates Growth Differentiation Factor-15 (GDF15) expression. Moreover, co-culture of compression-induced activated fibroblasts with pancreatic cancer cells significantly promotes cancer cell migration, which is inhibited by shRNA-mediated silencing of GDF15 in fibroblasts. Conclusively, our findings highlight the involvement of biophysical factors, such as solid stress, in tumor progression and malignancy revealing a novel role for GDF15.
This article was published in the following journal.
Name: Annals of biomedical engineering
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Subpopulation of heterogeneous fibroblasts within the TUMOR MICROENVIRONMENT that support NEOPLASTIC CELL TRANSFORMATION and NEOPLASTIC PROCESSES.
Tumors or cancer of the PANCREAS. Depending on the types of ISLET CELLS present in the tumors, various hormones can be secreted: GLUCAGON from PANCREATIC ALPHA CELLS; INSULIN from PANCREATIC BETA CELLS; and SOMATOSTATIN from the SOMATOSTATIN-SECRETING CELLS. Most are malignant except the insulin-producing tumors (INSULINOMA).
Star-shaped, myofibroblast-like cells located in the periacinar, perivascular, and periductal regions of the EXOCRINE PANCREAS. They play a key role in the pathobiology of FIBROSIS; PANCREATITIS; and PANCREATIC CANCER.
A 36-amino acid pancreatic hormone that is secreted mainly by endocrine cells found at the periphery of the ISLETS OF LANGERHANS and adjacent to cells containing SOMATOSTATIN and GLUCAGON. Pancreatic polypeptide (PP), when administered peripherally, can suppress gastric secretion, gastric emptying, pancreatic enzyme secretion, and appetite. A lack of pancreatic polypeptide (PP) has been associated with OBESITY in rats and mice.
Extracts prepared from pancreatic tissue that may contain the pancreatic enzymes or other specific uncharacterized factors or proteins with specific activities. PANCREATIN is a specific extract containing digestive enzymes and used to treat pancreatic insufficiency.
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