Osteopontin influences the invasiveness of pancreatic cancer cells and is increased in neoplastic and inflammatory conditions

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with an overall 5-year survival rate of less than 5%. Invasive tumor growth and early metastasis are two important reasons for this dismal prognosis. Osteopontin (OPN) is a secretory protein with a variety of functions, for example in cell adhesion and migration, inflammatory reaction and apoptosis. In this study the functional role of OPN in human pancreatic cancer and its potential use as a disease marker were analyzed. By real time quantitative PCR, there was a 2.2-fold and 1.6-fold increase of OPN mRNA in pancreatic cancers (n = 23) and chronic pancreatitis samples (n = 22), respectively, compared to normal pancreatic tissues (n = 20). Immunohistochemical analysis demonstrated OPN staining in 60% of the primary pancreatic tumors and in 72% of the lymph node and liver metastases. ELISA analysis of serum samples obtained from pancreatic cancer patients (n = 70), chronic pancreatitis patients (n = 12), and healthy donors (n = 20) showed a 1.6-fold increase in OPN serum levels in patients with tumors and a 1.9-fold increase in patients with chronic pancreatitis. Recombinant human OPN significantly increased the invasiveness of pancreatic cancer cells, without having any impact on cell proliferation. In addition, down regulation of OPN by specific siRNA molecules decreased pancreatic cancer cell invasion. In conclusion, OPN serum levels in pancreatic cancer and chronic pancreatitis patients are not significantly different, thereby restricting its role as a prognostic or follow-up marker. Our results do suggest, however, that blockade of OPN might be useful as a therapeutic approach to inhibit invasion and metastasis of pancreatic cancer cells.

Matricellular proteins osteopontin and osteonectin/SPARC in pancreatic carcinoma

“…Since previous studies showed that treatment of pancreatic cancer cell lines with exogenous osteopontin did not affect proliferation, these data suggest that endogenous levels of osteopontin in this cell line are necessary and sufficient for the support of tumor cell growth. 7,8 Since osteopontin can also increase the invasiveness of pancreatic carcinoma cells, these data reinforce the concept that osteopontin may be a target for therapeutic intervention. 8 The authors also demonstrate that knock down of osteonectin mRNA, using an antisense oligonucleotide, resulted in increased cell growth, whereas growth was suppressed by exogenously added osteonectin.…”

“…7,8 Since osteopontin can also increase the invasiveness of pancreatic carcinoma cells, these data reinforce the concept that osteopontin may be a target for therapeutic intervention. 8 The authors also demonstrate that knock down of osteonectin mRNA, using an antisense oligonucleotide, resulted in increased cell growth, whereas growth was suppressed by exogenously added osteonectin. These results are in concert with previously published data, suggesting that osteonectin plays a tumor suppressor role in PDA cells.…”

“…Numerous studies report the immunolocalization of osteopontin in the matrix and in association with PDA cells in human tissue samples. 8,11,12 However, in situ hybridization studies suggest that macrophages intimately associated with the tumor cells are the ones responsible for synthesizing osteopontin in this microenvironment. 13,14 It is suggested that the majority of osteopontin immunostaining of the adenoma cells may be due to association of osteopontin with the cell surface, through interaction with its receptor integrins or CD44.…”

Osteopontin but not osteonectin favors the metastatic growth of pancreatic cancer cell lines

“…47,[50][51][52][53][54] We found a 2.2-fold and 1.6-fold increase in OPN mRNA in pancreatic cancer and chronic pancreatitis samples, respectively, compared to normal pancreatic tissues. 9 The observed upregulation of both, ON and OPN in PDAC hints to a causal involvement of the two proteins. However, upregulation 'per se' is not sufficient to establish a tumor promoting effect, since it could also be interpreted as a defense mechanism.…”

“…Among those, the components of the extracellular matrix, osteonectin and osteopontin have been found to be upregulated in PDAC. 8,9 pancreatic ductal adenocarcinoma (pDaC) is the fourth leading cause of cancer-related death in western countries and among the malignancies with the worst prognosis. Osteonectin and osteopontin, two proteins of the extracellular matrix, have been found to be upregulated in pDaC.…”