Controlled degradation of the extracellular matrix by proteases is crucial in tumor cell invasion. We have shown that thrombospondin-1 (TSP-1), through activation of transforming growth factor beta-1 (TGF-beta1), regulates the plasminogen/plasmin protease system in breast cancer. To determine whether this occurred in other epithelial neoplasms, we studied the role of TSP-1 and TGF-beta1 in the regulation of the plasminogen/plasmin system in pancreatic cancer. ASPC-1 and COLO-357 pancreatic cancer cells were treated with TSP-1 or TGF-beta1 at varying concentrations. The TSP-1 and TGF-beta1-treated cells were also treated with either anti-TSP-1, anti-TSP-1 receptor, or anti-TGF-beta1 antibodies. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression was determined by enzyme-linked immunosorbent assay. TSP-1 and TGF-beta1 promoted a dose-dependent upregulation of ASPC-1 and COLO-357 PAI-1 expression. The TSP-1 effect could be blocked with anti-TSP-1 or anti-TGF-beta1 antibodies. The TGF-beta1 effect could be blocked only with anti-TGF-beta1 antibody. Anti-TSP-1 receptor antibody blocked the TSP-1 effect on PAI-1 expression but had no effect on TGF-beta1-mediated PAI-1 expression. Neither TSP-1 nor TGF-beta1 had an effect on uPA production. We conclude that TSP-1, in a receptor-mediated process that involves the activation of TGF-beta1, upregulates PAI-1 expression in pancreatic cancer without an effect on uPA production.

Antibodies, Neoplasm↗

PubMedDate not supplied

Co-localization of macrophage inflammatory protein-3alpha (Mip-3alpha) and its receptor, CCR6, promotes pancreatic cancer cell invasion.

PURPOSE: Macrophage inflammatory protein-3alpha (Mip-3alpha) is par t of a family of chemotactic cytokines involved in recruiting inflammatory cells throughout the body. CCR6 is a G-protein-linked, seven-transmembrane receptor that is highly specific for Mip-3alpha. The role of Mip-3alpha has been well defined in several inflammatory conditions, but its role has not been well defined in neoplastic processes. Mip-3alpha has been shown to promote pancreatic cancer cell migration, but no studies have demonstrated the effect of Mip-3alpha on pancreatic cancer cell invasion. We hypothesize that Mip-3alpha and its CCR6 receptor promote pancreatic cancer cell invasion. MATERIALS AND METHODS: Immunohistochemical staining was per formed for Mip-3alpha and CCR6 in pancreatic cancer tissue and the human pancreatic cancer cell line PANC-1. RNA was isolated from PANC-1 cancer cells, and the presence of Mip-3alpha messenger RNA in PANC-1 cancer cells was determined by reverse transcriptase polymerase chain reaction. PANC-1 cancer cell invasion of type IV collagen was evaluated in the presence of Mip-3alpha and anti-CCR6 antibody with the use of a modified Boyden chamber invasion assay. RESULTS: Co-localization of Mip-3alpha and its CCR6 receptor in pancreatic cancer was confirmed using immunohistochemical staining for Mip-3alpha and its CCR6 receptor and reverse transcriptase polymerase chain reaction for Mip-3alpha. Immunohistochemical staining of pancreatic cancer tissue and the PANC-1 cancer cell line showed positive staining for Mip-3alpha and its CCR6 receptor within the cancer cells. Staining was also positive for Mip-3alpha within stromal cells adjacent to the cancer cells in pancreatic cancer tissue. Reverse transcriptase polymerase chain reaction demonstrated the presence of Mip-3alpha messenger RNA within PANC-1 cancer cells. Invasion studies showed that increasing concentrations of Mip-3alpha promoted a dose-dependent increase in pancreatic cancer cell invasion of type IV collagen. The addition of 100 ng/mL of Mip-3alpha promoted a threefold increase in pancreatic cancer cell invasion over that of the control group. Anti-CCR6 antibody inhibited Mip-3alpha-stimulated PANC-1 cancer cell invasion of type IV collagen by 63%. DISCUSSION: Co-localization of Mip-3alpha and its CCR6 receptor promotes pancreatic cancer cell invasion of type IV collagen. This finding continues to highlight the importance that inflammation plays in the progression of pancreatic cancer. As the relationship between the inflammatory and neoplastic processes involved with pancreatic cancer becomes better defined, therapies targeting the inflammatory process may help prevent pancreatic cancer invasion and metastasis.

Adenocarcinoma↗

PubMedDate not supplied

Embolic and occlusive complications from thrombosed femorofemoral grafts.

Five episodes of acute arterial occlusions associated with thrombosed femorofemoral grafts are reported. Four of these occlusions were directly associated with trauma to the graft and were thought to be embolic. All patients had thrombus extending from the thrombosed graft into the femoral artery, threatening the survival of the lower extremity. We recommend that when a graft thrombectomy is not performed, or is not successful, the thrombosed femorofemoral graft should be detached or excised as prophylaxis against embolic and occlusive complications.

Adult↗