Study on the Alteration of E-cadherin in Gastric Cancers after Heat Shock/Hyperthermic Treatment, its Underlying Mechanism and Clinical Significance

• Main Author: 謝茂志
• Other Authors: Chia-Li Yu
• Format: Others
• Language: zh-TW
• Published: 2001
• Online Access: http://ndltd.ncl.edu.tw/handle/66471692037976978477

博士 === 國立陽明大學 === 臨床醫學研究所 === 89 === E-cadherin, a transmembrane glycoprotein with a molecular weight of 120 kDa, mediates homotypic and homophilic cell-cell adhesion. The breakdown product of E-cadherin, an 80 kDa soluble form of E-cadherin, enters circulation through proteolysis. When membranous E-cadherin expression is down regulated or absent on malignant cells, these cells may escape from the primary lesion and proceed to invade and metastate to the remote sites. In this study, we treated different gastric cancer cell lines with heat shock （42.5°C for 60 minutes）or proinflammatory cytokines (IL-1b and TNF-a). We found the expression of adhesion molecules such as CD29, CD54 and E-cadherin were enhanced on the surface of gastric cancer cells. This result indicates that heat shock has a potential to prevent the cancer from metastasis by alternation in E-cadherin expression on the cell surface. In addition, we noted that, the serum concentration of preoperative soluble E-cadherin (2555 ± 413 ng/ml) in patients with advanced gastric cancer is higher than that of normal control (1432 ± 426 ng/ml, p<0.001). Although the levels of serum soluble E-cadherin were not correlated to any clinicopathological factors of gastric cancer, it really correlated with the postoperative survival. The 5-year survival rate in patients with preoperative serum soluble E-cadherin levels higher than 2563 ng/ml was 36.4%, whereas the postoperative survival rate increased to 83.3% in those patients with serum soluble E-cadherin levels lower than 2563 ng/ml. The difference in survival rate is significant between the two groups (p=0.0148). These results suggest that the lower serum soluble E-cadherin presents postoperatively, the better the 5-year survival is. We selected a group of gastric cancer patients with peritoneal carcinomatosis for clinical effectiveness evaluation of hyperthermia therapy. We demonstrated that the postoperative levels of serum soluble E-cadherin are lower than the preoperative levels (2729 ± 234 ng/ml versus 2437 ± 333 ng/ml, p=0.008). The intraperitoneal hyperthermic treatment of the patients right after surgery reduced the postoperative serum soluble E-cadherin to a concentration of 1888 ± 406 ng/ml (preoperation: 2674 ± 305 ng/ml, p<0.001). The reduction of serum soluble E-cadherin in the patients treated with surgery alone was 292 ± 226 ng/ml, while the patients were treated with surgery followed by intraperitoneal hyperthermia was 789 ± 388 ng/ml (p<0.001). In the patients receiving surgery alone, the mean survival time was 8.74 months (1-16 months) and the 5-year survival rate was zero. However, combining surgery with intraperitoneal hyperthermic treatment (combination therapy), prolonged the mean survival time to 31.52 months (1-83 months) and the 5-year survival rate to 23.81%. For comparison, we further divided the patients receiving combination therapy into two subgroups. (I) The postoperative serum soluble E-cadherin concentration was higher than 1500 ng/ml, the mean survival time was 14.67 months (1-39 months) and the 5-year survival rate was zero. (II) The postoperative serum soluble E-cadherin concentration was lower than 1500 ng/ml, the mean survival time was 73.67 months (27-83 months) and the 5-year survival rate was 83.33%. In conclusion, heat shock increases the expression of E-cadherin on the surface of gastric cancer cells. The intraperitoneal hyperthermic treatment can reduce the postoperative concentration of serum soluble E-cadherin in these patients. Both alterations in E-cadherin expression are beneficial to the survival of patients with gastric cancer. The molecular basis and clinical implications of heat shock / intraperitoneal hyperthermic treatment are extendedly investigated in the present study. It is conceivable that the anti-cancer effects of heat shock might be related to, at least in part, the modulation of E-cadherin expression.