Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma

Department of Medicine, University of Washington, Seattle, WA, USA.
Cancer biology & therapy (Impact Factor: 3.07). 08/2012; 13(10):899-907. DOI: 10.4161/cbt.20842
Source: PubMed


The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.

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    • "While, Chung et al[48] perform a proteomic analysis between normal pancreas and PDAC and found Galectin-1 expression highly correlated to histology, T stage, N stage and AJCC stage. In agreement with findings of the other study [47], we found that staining intensity of Galectin-1 in stromal cells were significant associated with short patient survival, tumor stage and lymph node metastasis. In addition, the in vivo and vitro experiments also verified the PSCs derived Galectin-1 might increase the reproductive activity and invasion ability of pancreatic cancer cells[46], and facilitate the growth of the subcutaneous xenografts. "
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    ABSTRACT: Galectin-1, a member of carbohydrate-binding proteins with a polyvalent function on tumor progression, was found strongly expressed in pancreatic satellite cells (PSCs), which partner in crime with cancer cells and promote the development of pancreatic ductal adenocarcinoma (PDAC). We evaluated the effects of PSCs derived Galectin-1 on the progression of PDAC, as well as the tumor establishment and development in mouse xenografts. The relationship between immunohistochemistry staining intensity of Galectin-1 and clinicopathologic variables were assessed in 66 PDAC tissues, 18 chronic pancreatitis tissues and 10 normal controls. The roles of PSCs isolated from PDAC and normal pancreas on the proliferative activity, MMP2 and MMP9 expression, and the invasion of CFPAC-1 in the co-cultured system, as well as on the tumor establishment and development in mouse xenografts by mixed implanting with CFPAC-1 subcutaneously were evaluated. Galectin-1 expression was gradually increased from normal pancreas (negative), chronic pancreatitis (weak) to PDAC (strong), in which Galectin-1 expression was also increased from well, moderately to poorly differentiated PDAC. Galectin-1 staining intensity of pancreatic cancer tissue was associated with increase in tumor size, lymph node metastasis, perineural invasion and differentiation and UICC stage, and served as the independent prognostic indicator of poor survival of pancreatic cancer. In vitro and in vivo experiments indicated that TGF-β1 upregulated Galectin-1 expression in PSCs, which could further promotes the proliferative activity, MMP2 and MMP9 expression, and invasion of pancreatic cancer cells, as well as the tumor establishment and growth. Galectin-1 expression in stromal cells of pancreatic cancer suggests that this protein plays a role in the promotion of cancer cells invasion and metastasis and provides a therapeutic target for the treatment of pancreatic cancer.
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    • "Recent studies suggest that PSCs may also aid immune evasion. PSCs in the stroma of PanIN lesions and around cancer cells produce galectin-1, a β-galactoside-binding protein (Chen et al., 2012), that binds to N-acetyllactosamine on membrane glycoproteins and induces apoptosis in T cells thus suppressing the immune response (Tang et al., 2012). Ene-Obong et al. (2013) have reported that activated PSCs reduce the migration of CD8 positive T cells toward cancer cells in both human PDAC and the KPC mouse model of pancreatic cancer. "
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