title: Thrombospondin-2 inhibits tumor cell invasion through the modulation of MMP-9 and uPA in pancreatic cancer cells.
abstract: The extracellular matrix protein thrombospondin (TSP) plays an important role in a variety of biological processes, including cell-cell and cell-matrix interactions. The biological role of TSP-2 in invasion and metastasis is poorly understood, while it is known that TSP-1 regulates a proteolytic cascade that allows tumor cells to invade and metastasize. In this study, we examined the role of TSP-2 in tumor cell invasion and its association with proteolytic proteins, matrix metalloproteinase (MMP) and the plasminogen/plasmin system, including urokinase-type plasminogen activator (uPA), in the human pancreatic cancer cell line PANC-1. PANC-1 cells expressed a low level of TSP-2, but significant levels of TSP-1. We isolated three clones of PANC-1 transformants stably overexpressing human TSP-2 (PANC-T). PANC-T highly expressed the TSP-2 gene and protein, while TSP-1 expression was not altered. In vitro invasion assays demonstrated that the invasiveness of PANC-T clones was significantly suppressed (p<0.05; Welch test). Zymography revealed that restoration of TSP-2 synthesis in the PANC-T clones significantly inhibited MMP-9 activity (p<0.05; Welch test). uPA activity in the PANC-T clones was significantly suppressed (p<0.05; Welch test). We concluded that restoration of TSP-2 can inhibit cell invasion through the down-regulation of MMP-9 and uPA activity in pancreatic cancer cell lines. Thus, TSP-2 may be a potent inhibitor of metastasis in pancreatic cancer.
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Tokai University Hachioji Hospital, Tokyo 192-0032, Japan. nakamura.masato@hachioji-hosp.tokai.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Oida
authors.forename: Yoshyuki
authors.initials: Y
authors.lastname: Abe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Masaya
authors.initials: M
authors.lastname: Mukai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Matsuyama
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Chijiwa
authors.forename: Hozumi
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ueyama