Tissue inhibitor of metalloproteinase 1 as a biomarker of venous invasion in pancreatic ductal adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a poor prognosis. While venous invasion is believed to contribute to liver metastasis and an unfavorable prognosis, the precise mechanisms involved remain unclear. Here, we conducted gene expression profiling on eight PDAC tissue samples exhibiting portal venous invasion (VI group) compared to PDAC samples without portal venous invasion (CA group) and normal portal vein tissues (NV group). A subset of genes, including tissue inhibitor of metalloproteinase 1 (TIMP1), C-X-C motif chemokine receptor 4 (CXCR4), olfactomedin-like 2B (OLFML2B), and cytochrome P450 family 1 subfamily B member 1 (CYP1B1), was found to be specifically expressed in the PDAC group with venous invasion. Immunohistochemical staining of 15 cases revealed significantly higher levels of TIMP1 (P=.026) and CXCR4 (P<.001) in the VI set compared to the CA set. In addition, the PDAC group with strong TIMP1 expression had a higher frequency of lymphovascular invasion (P<.001) and lower 5-year survival rates than the PDAC group with no/weak TIMP1 expression (P=.027). Specific TIMP1 expression in the venous invasion foci was highlighted on 3D reconstruction imaging. Invasion assays and/or Western blot analyses were performed on pancreatic cancer cells (Panc1), cancer-associated fibroblasts (CAFs), and human endothelial cells (EA.hy926). TIMP1 inhibition suppressed cancer cell invasion in the presence of CAFs. TIMP1 expression increased with PI3Kp110, phospho-AKT, and phospho-ERK1/2 in Panc1 cells co-cultured with CAFs and EA.hy926 endothelial cells. Our data demonstrate that TIMP1 in pancreatic cancer cells promotes venous invasion of PDACs by activating the PI3K/AKT and ERK1/2 pathways in collaboration with CAFs and endothelial cells. Therefore, TIMP1 may serve as a biomarker for venous invasion in PDACs.