Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Abstract

Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the a 6 b 4 integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.

Periostin differentially induces proliferation, contraction and apoptosis of primary Dupuytren's disease and adjacent palmar fascia cells

“…Based on this estimate, and 1×10 5 DD or PF cells routinely yielding at least10 μg of total protein in our hands, the data was extrapolated to conclude that a treatment range of 0.5 to 2.0 μg/ml of recombinant periostin to 1×10 5 cells in culture would approximate in vivo levels. This range correlated with a previous report using 0.1 μg/ml to 5 μg/ml periostin to assess apoptosis in cultures of pancreatic cancer cells [37].…”

“…Myofibroblasts have been shown to utilize the PI3 kinase/Akt signaling pathway to avoid apoptosis in abnormal scarring [66][67][68] and periostin signaling has been shown to promote avoidance of apoptosis through this pathway [29,37]. While there was a consistent trend towards a decrease in DD cells apoptosis with periostin treatment, this did not achieve statistical significance in our in vitro collagen culture conditions (DD cells treated with vehicle vs. 0.5 μg/ml recombinant periostin, p=0.075; PF cells treated with vehicle vs. 2.0 μg/ml recombinant periostin, p=0.065).…”

Periostin, secreted from stromal cells, has biphasic effect on cell migration and correlates with the epithelial to mesenchymal transition of human pancreatic cancer cells

“…Consistently, quantitative real-time RT-PCR revealed that periostin was not or very faintly expressed in pancreatic cancer cell lines, but it was strongly expressed in PSC. 12,13 In agreement with these findings, we also showed much higher levels of both periostin mRNA and protein in stromal lesions compared with those in cancer cells. In addition, PSC expressed larger amounts of periostin than cancer cells did.…”

“…11 In addition, periostin has been suggested to promote the invasiveness or growth rate and confer resistance to hypoxia in pancreatic cancer cells, although the source of this protein was stromal cells rather than cancer cells. 12 It has been suggested that an interaction between cancer cells and stromal cells plays a pivotal role in cancer development since a pancreatic cancer cell supernatant stimulated the secretion of periostin from pancreatic satellite cells (PSC). 13 These findings raise the question of whether or not periostin can lead pancreatic cancer cells to the state of EMT through epithelial-mesenchymal interaction.…”

N-glycoprotein profiling of lung adenocarcinoma pleural effusions by shotgun proteomics

“…Periostin is a marker for metastatic lung and breast cancers, 13,16 and promotes invasion and metastatic growth in head and neck, 17 pancreatic, 18 and colon cancer, 19 and acts on the crosstalk between a m b 5 integrins and the EGF-receptor. 20,21 This protein is actually 1 of the most promising biomarkers, as its upregulation depends on the formation of desmoplastic stroma.…”