IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling

Background:

Interleukin-22 (IL-22) has been recently highlighted owing to its biological significance in the modulation of tissue responses during inflammation. However, the role of IL-22 in carcinogenesis has remained unclear. Here, we investigated the pathophysiological significance of IL-22 expression in gastric cancer tissues and examined the mechanism by which IL-22 promotes gastric cancer cell invasion.

Methods:

Human gastric cancer specimens were analysed by immunohistochemistry for expression of IL-22 and IL-22 receptor 1 (IL-22R1). The effects of IL-22-induced STAT3 and ERK signalling on invasive ability of gastric cancer cells were examined using a small-interfering RNA system and specific inhibitors. AGS cells were co-cultured with cancer-associated fibroblasts (CAFs) from human gastric cancer tissues and assessed by invasion assay.

Results:

Interleukin-22 and its receptor were expressed in α-smooth muscle actin-positive stromal cells and tumour cells at the invasive front of gastric cancer tissues, respectively. The expression of IL-22 and IL-22R1 was significantly related to lymphatic invasion. Interleukin-22 treatment promoted the invasive ability of gastric cancer cells through STAT3 and ERK activation. The invasive ability of gastric cancer cells was significantly enhanced by co-culture with IL-22-expressing CAFs.

Conclusions:

Interleukin-22 produced by CAFs promotes gastric cancer cell invasion via STAT3 and ERK signalling.     

Ursodeoxycholic acid stimulates the formation of the bile canalicular network

Ursodeoxycholic acid (UDCA) is a hepatoprotective bile acid used in the treatment of chronic liver diseases. Although several pharmacological effects, including choleresis and inhibition of apoptosis, have been proposed, the impact of UDCA on hepatic structure is not well understood. Here, the influence of UDCA on bile canalicular (BC) morphology was evaluated in vitro in immortalized rat hepatocytes (McA-RH 7777 cells) and primary rat hepatocytes. Cells cultured for 3 days in the presence of UDCA, the BC lumen was enlarged and the bile canaliculi were surrounded by multiple cells (≥5) with a continuous canal-like structure, reminiscent of the in vivo BC network. The effects were dependent on p38MAPK and conventional PKC in McA-RH cells, and partially dependent on p38MAPK, MAPK/ERK kinase, and conventional PKC in primary rat hepatocytes. These findings were then studied in vivo in a rat model of dimethylnitrosamine-induced hepatic injury, in which the BC network is significantly disrupted. In accordance with the in vitro observations, administration of UDCA (40mg/kg/day) to the injured rats for 18 days improved the BC network compared with the vehicle control. Serum hepatic markers were not altered by UDCA treatment, suggesting that the morphological effects were due to the direct actions of UDCA on network formation. Our data provide new evidence of the pharmacological potential of UDCA in accelerating or regenerating BC network formation in vitro, in hepatic cell culture models, and in vivo in a rat model of hepatic injury, and provide a basis for understanding its hepatoprotective effects.     

Present state and prospects of adjuvant chemotherapy for gastric cancer

In Japan, a one-year administration of S-1 is the standard adjuvant treatment for stage II/III gastric cancer after curative gastrectomy with a D2 lymph-node dissection.The treatment is recommended in the Japanese Guidelines for Treatment of Gastric Cancer(3rd Edition).Using data from results of a 5-year follow-up of the ACTS-GC trial, it was confirmed that using S-1 significantly improves the 5-year overall survival over surgery alone.However, the recurrence rate of stage III gastric cancer is still too high.More powerful treatment using multiple drugs is needed for this disease.This paper presents a new perspective for the development of post-operative adjuvant chemotherapy in the future, based on clinical trials recently reported.     

The Clinical Significance of Vimentin-Expressing Gastric Cancer Cells in Bone Marrow

Background  

Expression of the mesenchymal marker gene vimentin (VIM) in gastric cancer is associated with a more aggressive form of the disease and poor prognosis. Because epithelial mesenchymal transition (EMT) plays a critical role in the progression of gastric cancer, VIM expression was examined in the bone marrow (BM) of gastric cancer patients.     

Cancer of the gastric stump following distal gastrectomy for cancer

BACKGROUND: Cancer of the gastric stump (CGS) after distal gastrectomy for cancer has not been characterized in a large study. The aim of this study was to investigate the clinicopathological features and outcome of CGS following distal gastrectomy for cancer. METHODS: Patients with CGS following distal gastrectomy for gastric cancer diagnosed between 1970 and 2002 were reviewed retrospectively. RESULTS: A total of 108 patients was identified. The median interval between the initial gastrectomy and resection for CGS was 7.5 (range 1-41) years. The depth of tumour invasion was T1 in 67 patients, T2 in 16, T3 in eight and T4 in 17 patients. Endoscopic mucosal resection was performed in 25 patients with T1 tumours. R0 resection was achieved in 103 patients. The overall 5-year survival rate was 53.1 per cent. The 5-year survival rates for patients with T1, T2, T3 and T4 disease were 76, 40, 13 and 9 per cent respectively. CONCLUSION: The outcome for patients with non-early CGS was poor. Early detection of CGS is important following distal gastrectomy for gastric cancer and strict surveillance is recommended for at least 10 years after the initial gastrectomy.     

Risk factors for para-aortic lymph node metastasis of gastric cancer from a randomized controlled trial of JCOG9501

BACKGROUND: No risk factor has been confirmed for para-aortic lymph node (PAN) metastasis from gastric cancer. To identify the risk factors and the most frequent route of metastasis to PAN, we analyzed the prospective data from a phase III trial. METHODS: In JCOG9501 comparing D2 and D2 + PAN dissection, 260 patients with T2(SS)-T4 gastric cancer underwent radical gastrectomy with PAN dissection. The association between various clinicopathological factors and PAN metastasis was examined. RESULTS: Macroscopic N stage and tumor size > or = 5 cm were significant risk factors for PAN metastasis after adjusting for other factors. The proportion of PAN metastasis was clearly different between the N0-1 group and the N2-4 group (2.8% versus 20.5%). In the additional multivariate analysis including 17 regional lymph node stations, station No. 7 was the only station with statistical significance (P = 0.002, odds ratio = 41.0). CONCLUSION: Macroscopic N stage and tumor size were associated with PAN metastasis, and the lymphatics along the left gastric artery seemed to be the most frequent route to the nodes surrounding the aorta. These findings may be useful in predicting PAN metastasis.