title: Tissue invasive macrophage density is correlated with prognosis in cholangiocarcinoma.
abstract: Cholangiocarcinoma (CCA) is a high metastatic cancer with no effective treatment. Here, the pro-metastatic action of tissue macrophages in CCA is demonstrated and suggested as a prognostic marker and novel target for the therapeutic intervention of CCA. Fifty CCA tissues were immunohistochemically stained with a marker for reactive/infiltrating monocytes/macrophages (MAC387) and matrix metalloproteinase (MMP)-9. The antigenic densities in positively-stained cells along the leading edge of tumors were scored. Correlations between the densities of MAC387, MMP-9-positive cells, clinicopathological features and patient survival were investigated. High densities of MAC387-positive cells were detected in more than 60% of the CCA tissues. This was significantly associated with poor prognosis parameters (non-papillary and mass-forming type CCA). Overall survival was worst in patients with high-density MAC387-positive cells. Double immunofluorescent staining indicated that MAC387-positive cells co-expressed MMP-9. Immunohistochemical staining of MMP-9 in serial sections of CCA tissues indicated that MMP-9 was rarely expressed in CCA tumor cells, but highly expressed in MAC387-positive cells and polymorphonucleated infiltrating cells. Patients with high tissue expression levels of MAC387 in combination with MMP-9-expressing cells had the worst survival. These factors were found to be independent predictors of the post-resectional survival of CCA patients. Since CCA tumor cells rarely expressed MMP-9, it is likely that tissue macrophages are critical for degrading the extracellular matrix and for facilitating tumor metastasis. They may therefore serve as a prognostic marker for poor clinical outcome, and represent novel targets for the therapeutic intervention of CCA.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Chutima
authors.initials: C
authors.lastname: Subimerb
authors.forename: Somchai
authors.initials: S
authors.lastname: Pinlaor
authors.forename: Narong
authors.initials: N
authors.lastname: Khuntikeo
authors.forename: Chanvit
authors.initials: C
authors.lastname: Leelayuwat
authors.forename: Alanna
authors.initials: A
authors.lastname: Morris
authors.forename: Michael S
authors.initials: MS
authors.lastname: McGrath
authors.forename: Sopit
authors.initials: S
authors.lastname: Wongkham