PPARgamma Ligand-Induced Decrease of in vivo Tumor Growth Accompanied by Increased Cytolytic Activity of Splenocytes

BACKGROUND: Recent studies have proposed the use of peroxisome proliferator activated receptor-gamma (PPARgamma) ligands as new chemotherapeutic agents for human malignant tumors. However the in vivo mechanism of PPARgamma ligands on cellular toxicity is not clear. Therefore we examined the anti-tumor effects of the PPARgamma ligand, rosiglitazone (ROS), in animal models. METHODS: To evaluate the effect of RSO on splenocytes, an in vitro and in vivo study was performed. Cytolytic activity was measured by use of a 51Cr release assay. The splenic natural killer (NK) cell population and effector-target conjugation were measured by flow cytometric analysis. RESULTS: In 9L glioma bearing rats, 30 mg/kg/d of ROS treatment induced a significant decrease of subcutaneous tumor growth accompanied by an increased cytolytic activity of splenocytes and of the splenic NKR-P1bright/CD3- NK cell population. In normal rats, systemic administration of ROS also increased the cytolytic activity of splenocytes, the splenic NK cell population, and effector-target conjugation. Moreover, we found that a concentration of 20micrometer ROS caused an increase in the cytolytic activity of splenocytes, and a concentration of 50micrometer ROS increased effector-target conjugation in vitro. CONCLUSIONS: These results suggest that increased splenic cytolytic activity and NK cell population may contribute to the anti-tumor effects of PPARgamma ligands in vivo. However, the roles of NK cells in the PPARgamma ligand-induced anti-tumor activity should be further investigated.

Expression of Angiopoietin 1, 2 and Their Common Receptor Tie2 in Human Gastric Carcinoma: Implication for Angiogenesis

Angiogenesis, formation of new microvessels providing oxygen and nutrient supply, is essential for tumor growth. It is dependent on the production of angiogenic growth factors by tumor cells. Angiopoietin 1 (Ang-1) and 2 (Ang-2) and their common receptor, Tie2, are thought to be critical regulators of tumor angiogenesis. We examined expression of Ang-1, Ang-2, and their common receptor Tie2 mRNAs and proteins in gastric cancers using in situ hybridization and immunohistochemistry. We also investigated the relationship between their expression and differentiation of cancer cells, lymph node metastasis, tumor size, depth of cancer cell invasion, TNM staging and microvessel density (MVD). The expression of Ang-1, Ang-2, and Tie2 mRNA in cancer cells significantly correlated with the MVD (p<0.001, <0.001 and =0.019, respectively). Ang-1 and Tie2 positivity correlated with advanced gastric cancers (p<0.05) and larger cancers had higher positive rates of Ang-1, Ang-2, and Tie2 mRNA expression (p<0.001, =0.010 and =0.039, respectively). Significant positive correlations were also found between mRNA expression of Tie2 and those of Ang-1 and Ang-2 (p<0.01 and <0.001, respectively). These findings indicate that the expression of Ang-1 and Ang-2 is important for tumor angiogenesis, and suggest a possible role of autocrine/paracrine function of angiopoietin/Tie2 system in gastric cancer progression.

Expression of Vascular Endothelial Growth Factors A,C and D in Gastric Adenocarcinoma

BACKGROUND: Vascular endothelial growth factor (VEGF)-C and VEGF-D are novel growth factors that regulate lymphatic vessel growth. This study was designed to examine whether the expression of three VEGF family members, VEGF-A, VEGF-C and VEGF-D are associated with the clinicopathologic parameters, especially with lymph node metastasis, in advanced gastric carcinomas. METHODS: Immunohistochemical staining was performed for VEGF-A, VEGF-C, and VEGF-D in the surgically resected specimens from 102 patients with advanced gastric carcinoma. The mRNA expressions of the three VEGF family members were assessed in 16 cases of tumor tissues and their corresponding non-neoplastic tissues. RESULTS: Of the 102 gastric carcinomas, 74 (73%), 82 (80%), and 34 (33%) cases showed cytoplasmic immunoreactivity for VEGF-A, VEGF-C and VEGF-D, respectively. Both VEGF-A and VEGF-C expressions were associated with lymphatic invasion and lymph node metastasis (p0.05). In the tumor tissue, VEGF-C mRNA expression was greater, while VEGF-D mRNA expression was lower than in the nonneoplatic tissue adjacent to the tumor. CONCLUSIONS: VEGF-A and VEGF-C may play important roles for the lymphatic spread of gastric carcinoma. We suggest that neutralizing both VEGF-A and VEGF-C may be reguired to block lymph node metastasis.

Expression of Transforming Growth Factor-beta and Its Receptors during Acetic Acid-induced Duodenal Ulcer Healing in Rats

BACKGROUND: Many works have been written about the transforming growth factor-beta 1 (TGF-beta1) which is closely associated with fibrosis in the inflammatory conditions of different organs. TGF-beta1 exerts its biological effects by interacting with specific cell surface receptors, namely, transforming growth factor-beta receptor type I and II (TGFbetaRI and TGFbetaRII). METHODS:To investigate the temporal expressions and localizations of TGF-beta1, TGFRbetaI, and TGFbetaRII in acetic acid-induced duodenal ulcerated tissues, we performed in situ hybridization and immunohistochemical techniques. RESULTS: Under in situ hybridization, TGF-beta1, TGFbetaRI, and TGFbetaRII mRNA signals increased in the experimental groups (1, 3, 7, and 14 day groups) compared to those of the control group. The signals on day 14 decreased slightly compared to those of days 1, 3, and 7, but they were higher than those of the control group. Under immunohistochemical study, TGF-beta1, TGFbetaRI, and TGFbetaRII were localized in the mucosal epithelial cells and in the macrophages, vascular endothelial cells, and fibroblasts of the lamina propria and granulation tissue. As in the case of the in situ hybridization, it revealed that the expression of three proteins increased in the experimental groups compared to that of the control group. The expression on day 14 decreased compared to those of days 1, 3, and 7, but it was more intense than that of the control group. CONCLUSIONS: This study suggests that TGF-beta1, TGFbetaRI, and TGFbetaRII contribute to the early stage healing of duodenal ulcer.