Low-dose paclitaxel modulates tumour fibrosis in gastric cancer.

Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-ß (TGF-ß) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-ß signalling pathway. The TGF-ß/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-ß/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused significant inhibition of TGF-ß1-induced morphological changes in human peritoneal methothelial cells on pre-treatment with PTX was 5 nM at 48 h (cell viability: 87.1±1.5%, P<0.01). The TGF-ß signalling cascade and the status of various fibrous components were evaluated by immunofluorescence staining, real-time quantitative PCR and western blotting. TGF-ß signalling induced morphological changes, α-SMA expression and collagen I synthesis in HPMCs and PTX treatment suppressed these EMT-like changes. Moreover, PTX treatment markedly suppressed Smad2 phosphorylation. These data suggest that at a low-dose, PTX can significantly suppress the TGF-ß/Smad signalling pathway by inhibiting Smad2 phosphorylation in the human peritoneum and that this can reduce stromal fibrosis.

Adiponectin receptor-1 expression is associated with good prognosis in gastric cancer.

BACKGROUND: Adiponectin is inversely related to BMI, positively correlates with insulin sensitivity, and has anti-atherogenic effects. In recent years, adiponectin has been well studied in the field of oncology. Adiponectin has been shown to have antiproliferative effects on gastric cancer, and adiponectin expression is inversely correlated with clinical staging of the disease. However, no studies have reported the correlation between serum adiponectin and receptor expression with disease progression. METHODS: In this study, we evaluated expression levels of 2 adiponectin receptors--AdipoR1 and AdipoR2--and attempted to correlate their expression with prognosis in gastric cancer patients. AdipoR1 and AdipoR2 expression in gastric cancer cell lines (MKN45, TMK-1, NUGC3, and NUGC4) was evaluated by western blotting analysis, and the antiproliferative potential of adiponectin was examined in vitro. Serum adiponectin levels were evaluated in 100 gastric cancer patients, and the expression of AdipoR1 and AdipoR2 was assessed by immunohistochemical staining. RESULTS: MKN45 and NUGC3 expressed higher levels of AdipoR1 compared to NUGC4, even though there was no significance in AdipoR2 expression. The antiproliferative effect of adiponectin was confirmed in MKN45 and NUGC3 at 10 µg/ml. No significant associations were observed between serum adiponectin levels and clinicopathological characteristics, but lymphatic metastasis and peritoneal dissemination were significantly higher in the negative AdipoR1 immunostaining group (24/32, p = 0.013 and 9/32, p = 0.042, respectively) compared to the positive AdipoR1 group (lymphatic metastasis, 33/68; peritoneal dissemination, 8/68). On the other hand, AdipoR2 expression was only associated with histopathological type (p = 0.001). In survival analysis, the AdipoR1 positive staining group had significantly longer survival rates than the negative staining group (p = 0.01). However, multivariate analysis indicated that AdipoR1 was not an independent prognostic factor on patient's survival on gastric cancer. CONCLUSIONS: In gastric cancer, adiponectin has the possibility to be involved in cell growth suppression via AdipoR1. The presence of AdipoR1 could be a novel anticancer therapeutic target in gastric cancer.