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Abstract
Pancreatic ductal adenocarcinoma (PDAC) exists in a complex desmoplastic microenvironment. As part of it, pancreatic stellate cells (PSCs) provide a fibrotic niche, stimulated by a dynamic communication between activated PSCs and tumour cells. Investigating how PSCs contribute to tumour development and for identifying proteins that the cells secrete during cancer progression, we studied by means of complex antibody microarrays the secretome of activated PSCs. A large number of secretome proteins were associated with cancer-related functions, such as cell apoptosis, cellular growth, proliferation and metastasis. Their effect on tumour cells could be confirmed by growing tumour cells in medium conditioned with activated PSC secretome. Analyses of the tumour cells’ proteome and mRNA revealed a strong inhibition of tumour cell apoptosis, but promotion of proliferation and migration. Many cellular proteins that exhibited variations were found to be under the regulatory control of eukaryotic translation initiation factor 4E (eIF4E), whose expression was triggered in tumour cells grown in the secretome of activated PSCs. Inhibition by an eIF4E siRNA blocked the effect, inhibiting tumour cell growth in vitro. Our findings show that activated PSCs acquire a pro-inflammatory phenotype and secret proteins that stimulate pancreatic cancer growth in an eIF4E-dependent manner, providing further insight into the role of stromal cells in pancreatic carcinogenesis and cancer progression.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in Western Europe and North America and the number of deaths is bound to grow even further[1]
With the eukaryotic translation initiation factor 4E, a protein was found whose expression was triggered by conditioning with secretome of activated pancreatic stellate cells (PSCs) and which is involved in the control of many of the identified protein variations in the tumour cells
The same was observed for extracellular matrix protein (ECM) proteins, such as FN-1 and Col-1 (Fig. 2), which are known to be preferentially expressed by activated PSCs and reported to be involved functionally in cell proliferation and angiogenesis[29]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in Western Europe and North America and the number of deaths is bound to grow even further[1]. The most common marker of reactive stroma in pancreatic cancer is the transformation of pancreatic stellate cells (PSCs) to myofibroblast-like cells This cell type is characterised by the ability to express α-smooth muscle actin (α-SMA), an increased proliferation and secretion of fibrogenic cytokines[6]. With the eukaryotic translation initiation factor 4E (eIF4E), a protein was found whose expression was triggered by conditioning with secretome of activated PSCs and which is involved in the control of many of the identified protein variations in the tumour cells. This regulatory process was confirmed by functional studies.
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