Abstract
BackgroundPancreatic cancer shows a highly aggressive and infiltrative growth pattern and is characterized by an abundant tumor stroma known to interact with the cancer cells, and to influence tumor growth and drug resistance. Cancer cells actively take part in the production of extracellular matrix proteins, which then become deposited into the tumor stroma. Type IV collagen, an important component of the basement membrane, is highly expressed by pancreatic cancer cells both in vivo and in vitro. In this study, the cellular effects of type IV collagen produced by the cancer cells were characterized.MethodsThe expression of type IV collagen and its integrin receptors were examined in vivo in human pancreatic cancer tissue. The cellular effects of type IV collagen were studied in pancreatic cancer cell lines by reducing type IV collagen expression through RNA interference and by functional receptor blocking of integrins and their binding-sites on the type IV collagen molecule.ResultsWe show that type IV collagen is expressed close to the cancer cells in vivo, forming basement membrane like structures on the cancer cell surface that colocalize with the integrin receptors. Furthermore, the interaction between type IV collagen produced by the cancer cell, and integrins on the surface of the cancer cells, are important for continuous cancer cell growth, maintenance of a migratory phenotype, and for avoiding apoptosis.ConclusionWe show that type IV collagen provides essential cell survival signals to the pancreatic cancer cells through an autocrine loop.
Highlights
Pancreatic cancer shows a highly aggressive and infiltrative growth pattern and is characterized by an abundant tumor stroma known to interact with the cancer cells, and to influence tumor growth and drug resistance
Type IV collagen is highly expressed in the stroma of pancreatic cancer when compared to other basement membrane proteins The expression of type IV collagen and other basement membranes (BM) proteins was studied by immunofluorescence in normal pancreas and pancreatic cancer tissue
Type IV collagen is highly expressed in close proximity to the pancreatic cancer cells and colocalizes with integrin α1, α2, and β1 on the cancer cell surface The expression pattern of type IV collagen in relation to the integrin receptors known to bind type IV collagen (α1β1 and α2β1) was examined with immunofluorescence both in normal pancreas and in pancreatic cancer tissue
Summary
Pancreatic cancer shows a highly aggressive and infiltrative growth pattern and is characterized by an abundant tumor stroma known to interact with the cancer cells, and to influence tumor growth and drug resistance. The cellular effects of type IV collagen produced by the cancer cells were characterized. The five-year survival rate has only improved marginally over the past decades, and remains at less than 5% [1,2]. Pancreatic cancer has the lowest long-term survival rate among the common malignancies. The disease typically displays an aggressive, rapid and infiltrative growth pattern, with metastases often already seeded at the time of diagnosis. Pancreatic cancer is characterized by an abundant fibrotic tumor stroma, referred to as the desmoplastic reaction, which surrounds and infiltrates clusters of cancer cells.
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