CD271+ Subpopulation of Pancreatic Stellate Cells Correlates with Prognosis of Pancreatic Cancer and Is Regulated by Interaction with Cancer Cells

Abstract

Pancreatic stellate cells (PSCs) play a crucial role in the aggressive behavior of pancreatic cancer. Although heterogeneity of PSCs has been identified, the functional differences remain unclear. We characterized CD271+ PSCs in human pancreatic cancer. Immunohistochemistry for CD271 was performed for 31 normal pancreatic tissues and 105 pancreatic ductal adenocarcinomas (PDACs). We performed flow cytometry and quantitative RT-PCR, and assessed CD271 expression in PSCs isolated from pancreatic tissues and the changes in CD271 expression in PSCs cocultured with cancer cells. We also investigated the pattern of CD271 expression in a SCID mouse xenograft model. In the immunohistochemical analyses, the CD271-high staining rates in pancreatic stroma in normal pancreatic tissues and PDACs were 2/31 (6.5%) and 29/105 (27.6%), respectively (p = 0.0069). In PDACs, CD271+ stromal cells were frequently observed on the edge rather than the center of the tumors. Stromal CD271 high expression was associated with a good prognosis (p = 0.0040). Flow cytometric analyses demonstrated CD271-positive rates in PSCs were 0–2.1%. Quantitative RT-PCR analyses revealed that CD271 mRNA expression was increased in PSCs after coculture with pancreatic cancer cells. However, the level of CD271 mRNA expression subsequently decreased after the transient increase. Furthermore, CD271 mRNA expression was decreased in PSCs migrating toward pancreatic cancer cells through Matrigel. In the xenograft model, CD271+ PSCs were present at tumor margins/periphery and were absent in the tumor core. In conclusion, CD271 was expressed in PSCs around pancreatic tumors, but not in the center of the tumors, and expression decreased after long coculture with pancreatic cancer cells or after movement toward pancreatic cancer cells. These findings suggest that CD271+ PSCs appear at the early stage of pancreatic carcinogenesis and that CD271 expression is significantly correlated with a better prognosis in patients with PDAC.

Galanin plays an important role in cancer invasiveness and is associated with poor prognosis in stage II colorectal cancer

“…Each experiment was carried out in triplicate wells and independent experiments were repeated. Invasive cells were isolated by functional separation using the Matrigel invasion assay after 72 h in culture ( 22 ).…”

Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives

“…The finding that PSC express Meflin indicates shared features between these two cell types, details of which should be investigated in the future. Moreover, a previous study has shown that CD271 (also known as nerve growth factor receptor), a marker of PSC and MSC, is expressed by stromal cells in PDAC and the number of CD271 + cells is associated with a better prognosis, further supporting a view that PSC are closely related to MSC . However, it remains unclear whether Meflin + CAF and CD271 + stromal cells are the same or represent distinct cell populations.…”

Functional heterogeneity in tumor-derived human pancreatic stellate cells: Differential expression of HGF and implications for mitogenic signaling and migration in pancreatic cancer cells

“…Heterogeneity among PSCs within the same tumor has been observed, suggesting that various subsets of PSCs have different effects on cancer cell migration and proliferation [ 18 ] and on outcome in patients [ 19 ]. Although relatively few data exist on functional heterogeneity of stromal cells, the possibility of heterogeneity among PSC populations isolated from different patients has been put forward, indicating that different PCS phenotypes could interact differently with the cancer cells in the tumor microenvironment [ 5 ].…”