Pancreatic Stellate Cells Potentiate Proinvasive Effects of SERPINE2 Expression in Pancreatic Cancer Xenograft Tumors

We have previously reported that inducible overexpression of the serine protease inhibitor nexin 2 (SERPINE2) significantly increases local invasiveness of subclones of the pancreatic cancer cell-line SUIT-2 in nude mouse xenografts. This was associated with a striking increase of extracellular matrix deposition in the invasive tumors. Pancreatic stellate cells (PSCs) have recently been identified as the major source of fibrosis in pancreatic adenocarcinomas. Here we report that co-injection of PSCs and tumor cells dramatically enhances the invasive potential of serine protease inhibitor Nexin 2 (SERPINE2)-expressing SUIT-2 cells. 100% (24 of 24) of the SERPINE2-expressing tumors with PSCs grew aggressively invasive, as compared to 39% of SERPINE2-negative tumors with PSCs and 27% of SERPINE2-expressing tumors without PSCs. In contrast to pure cancer cell preparations, SERPINE2 overexpression in the presence of PSCs also resulted in increased tumor growth. Histological evaluation demonstrated the presence of large amounts of ECM deposits co-localizing with cells staining positive for the PSC marker α-SMA. We conclude that PSCs actively proliferate in pancreatic cancer xenograft tumors and significantly contribute to the local invasive potential of the tumors. Presence of PSCs enhances the pro-invasive effects of SERPINE2 expression, and SERPINE2 influences tumor growth (as opposed to invasiveness) only in the presence of PSCs. Our data thus suggest that SERPINE2 is an important modulator of tumor cell/host interactions in pancreatic cancer.