ABSTRACT
BACKGROUND: Although secretory phospholipase A2 (sPLA2) has been shown to be involved in various biological processes, its specific roles in sub-types of cancer development remain to be elucidated. MATERIALS AND METHODS: We examined the expression of sPLA2 group III (GIII) in 142 patients with colorectal cancer using immunohistochemistry, and its correlation with clinicopathological features and outcomes. In addition, we examined the co-expression of sPLA2GIII and sPLA2GX using serial tissue sections to clarify the roles of both proteins in colorectal carcinogenesis. RESULTS: In 66 cases, diffuse staining of sPLA2GIII was seen; this was defined as the group with high expression. High expression was associated with a significantly higher rate of lymph node metastasis (p=0.02) and poorer survival (p=0.03) compared with low expression. Patients with low sPLA2GIII and high sPLA2GX expression had a significantly higher survival rate than those with high sPLA2GIII and low sPLA2GX expression (p=0.038). CONCLUSION: sPLA2GIII expression may be used as a risk factor for lymph node metastasis and a prognostic marker in colorectal cancer. In addition, sPLA2GIII and sPLA2GX may play opposing roles in colorectal carcinogenesis.
Subject(s)
Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , Group III Phospholipases A2/genetics , Group X Phospholipases A2/genetics , Adult , Aged , Colorectal Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Group III Phospholipases A2/biosynthesis , Group X Phospholipases A2/biosynthesis , Humans , Lymphatic Metastasis , Male , Middle Aged , Prognosis , Risk Factors , Survival RateABSTRACT
Angiogenesis and lymphangiogenesis mediated by vascular endothelial growth factors (VEGFs) are main features of chronic inflammation and tumors. Secreted phospholipases A(2) (sPLA(2)s) are overexpressed in inflammatory lung diseases and cancer and they activate inflammatory cells by enzymatic and receptor-mediated mechanisms. We investigated the effect of sPLA(2)s on the production of VEGFs from human macrophages purified from the lung tissue of patients undergoing thoracic surgery. Primary macrophages express VEGF-A, VEGF-B, VEGF-C, and VEGF-D at both mRNA and protein level. Two human sPLA(2)s (group IIA and group X) induced the expression and release of VEGF-A and VEGF-C from macrophages. Enzymatically-inactive sPLA(2)s were as effective as the active enzymes in inducing VEGF production. Me-Indoxam and RO092906A, two compounds that block receptor-mediated effects of sPLA(2)s, inhibited group X-induced release of VEGF-A. Inhibition of the MAPK p38 by SB203580 also reduced sPLA(2)-induced release of VEGF-A. Supernatants of group X-activated macrophages induced an angiogenic response in chorioallantoic membranes that was inhibited by Me-Indoxam. Stimulation of macrophages with group X sPLA(2) in the presence of adenosine analogs induced a synergistic increase of VEGF-A release and inhibited TNF-alpha production through a cooperation between A(2A) and A(3) receptors. These results demonstrate that sPLA(2)s induce production of VEGF-A and VEGF-C in human macrophages by a receptor-mediated mechanism independent from sPLA(2) catalytic activity. Thus, sPLA(2)s may play an important role in inflammatory and/or neoplastic angiogenesis and lymphangiogenesis.
Subject(s)
Group II Phospholipases A2/physiology , Group X Phospholipases A2/physiology , Lung/enzymology , Lung/immunology , Macrophages, Alveolar/enzymology , Macrophages, Alveolar/immunology , Vascular Endothelial Growth Factors/biosynthesis , Animals , Catalysis , Chick Embryo , Chorioallantoic Membrane/blood supply , Chorioallantoic Membrane/enzymology , Chorioallantoic Membrane/metabolism , Group II Phospholipases A2/biosynthesis , Group II Phospholipases A2/metabolism , Group X Phospholipases A2/biosynthesis , Group X Phospholipases A2/metabolism , Humans , Inflammation Mediators/physiology , Lung/cytology , Lung/pathology , Lymphangiogenesis/immunology , Macrophages, Alveolar/cytology , Macrophages, Alveolar/pathology , Neovascularization, Pathologic/enzymology , Neovascularization, Pathologic/immunology , Neovascularization, Pathologic/metabolism , Neovascularization, Physiologic/immunology , Protein Isoforms/biosynthesis , Protein Isoforms/metabolism , Protein Isoforms/physiology , Receptor, Adenosine A3/physiology , Vascular Endothelial Growth Factor A/biosynthesis , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/physiology , Vascular Endothelial Growth Factor C/biosynthesis , Vascular Endothelial Growth Factor C/metabolism , Vascular Endothelial Growth Factor C/physiologyABSTRACT
Secretory phospholipase A2 (sPLA2) type IIA and X was analyzed in tumors from 22 patients with colon adenocarcinomas in order to determine the involvement and activity of sPLA2 in colon cancer. Evaluation of immunoreactive sPLA2 IIA by Western blotting showed a significantly higher level in the periphery of the tumors, compared to central tumor regions. Increased levels of sPLA2 IIA protein correlated with a two-fold increase in sPLA2 enzymatic activity in the peripheral regions compared to central regions. Nineteen out of 22 tumors showed high levels of sPLA2 IIA, whereas 7 out of the 22 tumors showed sPLA2 type X. These data demonstrate that both sPLA2 type IIA and X are present in human colon cancer and suggest a role for sPLA2 in colon cancer tumor immunology and tumorigenesis.
