Tissue invasive macrophage density is correlated with prognosis in cholangiocarcinoma

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Molecular Medicine Reports (Impact Factor: 1.55). 07/2010; 3(4):597-605. DOI: 10.3892/mmr_00000303
Source: PubMed


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.

Download full-text


Available from: Chanvit Leelayuwat
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammation as a risk factor for cancer development is driven in part by monocyte/macrophages, which in many cancers exhibit pro-tumorigenic activity. In this study we identified elevation in CD14(+) CD16(+) , a minor blood monocyte subpopulation in cholangiocarcinoma (CCA) patients, compared to normal and biliary disease patient specimens. Tumour association was suggested by the observation that this elevated level decreased to normal after tumour resection. Moreover, the elevated level of CD14(+) CD16(+) monocytes in CCA patient blood correlated with degree of MAC387-positive (recent blood-derived macrophage migrant-specific marker) tumour-associated macrophage infiltration as determined by immunohistochemistry. These CD14(+) CD16(+) monocytes were suggested to enhance tumour progression as this subpopulation possesses (i) high expression of adhesion molecules (CD11c, CD49d, and CD54) and scavenger receptor (CD163), which enable them to adhere strongly to endothelial cells, and (ii) that peripheral blood monocytes from CCA patients express high levels of growth and angiogenic factor-related genes (epiregulin, VEGF-A and CXCL3). Elevation of peripheral CD14(+) CD16(+) monocyte levels was associated with features associated with poor prognosis CCA parameters (non-papillary type and high number of tissue macrophages). These data indicate that the CD14(+) CD16(+) monocytes from CCA patients with pro-tumorigenic characteristics may associate with rapid tumour progression and poor patient outcome. If confirmed in subsequent studies, the level of CD14(+) CD16(+) monocytes may serve as a marker for disease activity in CCA patients and serve as a target for pathogenic macrophage specific drug development.
    Full-text · Article · Sep 2010 · Clinical & Experimental Immunology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cholangiocarcinoma (CCA) is a rare type of liver cancer with a very poor prognosis. The prevalence of CCA is markedly variable with the highest incidence in the northeast Thailand, followed by other parts of Southeast Asia and China. Currently, there is still no reliable biomarker for diagnosis or treatment. NADPH-quinone oxidoreductase 1 (NQO1) is a xenobiotic metabolizing enzyme detoxifying chemical stressors and antioxidants, thereby providing cytoprotection in normal tissues. However, NQO1 is over-expressed in some cancers, suggesting roles in carcinogenesis and tumor progression. In this study, we examined NQO1 activity in surgical specimens from CCA patients and found much higher values than in the adjacent normal tissues. Immunohistochemical analysis revealed strong staining in tumor epithelial elements, whereas the non-tumor bile ducts and liver parenchyma were weakly stained. NQO1 mRNA expression in tumor tissues was widely varied among 43 patients. A significant association was observed between high level of NQO1 expression and short overall survival time by the Cox proportional hazard ratio of 2.40, p<0.05. By histological classification, non-papillary adenocarcinoma was an independent predictor for poor prognosis with the hazard ratio of 2.79, p<0.05. NQO1 expression may serve as a prognostic biomarker for the CCA.
    No preview · Article · Jan 2012 · Asian Pacific journal of cancer prevention: APJCP
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Stromal-epithelial interactions are important for carcinogenesis. Once cancerous lesions develop, a chronically inflamed tumor microenvironment promotes migration and invasion of tumor cells. Multiple immune cell populations are involved in inflammatory processes, including tumor-associated macrophages (TAMs) which have been proposed as major contributors to tumor progression. The epithelial-mesenchymal transition (EMT) is a process in which epithelial cells trans-differentiate and acquire an invasive mesenchymal phenotype. As EMT represents a crucial step in disease progression, it is important to investigate the mechanisms regulating this step. We aimed to identify the profiles of cytokines produced by activated human macrophages and to demonstrate effects on the expression of EMT-related genes in human cholangiocarcinoma (CCA) cell lines. Our results showed that LPS-activated macrophages produced and secreted IL4, IL6, IL10, TNF-alpha and TGF-beta 1. After addition of macrophage conditioning media to CCA cells, expression of epithelial markers E-cadherin and CK-19 was significantly reduced, whereas the expression of mesenchymal markers, S100A4 and MMP9 was strongly induced. Taken together, various cytokines secreted by activated macrophages could induce EMT by altering the expression of EMT-related genes in CCA.
    Full-text · Article · Jan 2012 · Asian Pacific journal of cancer prevention: APJCP
Show more