Gene expression changes induced by HIPEC in a murine model of gastric cancer

Abstract

Background: Peritoneal carcinogenesis (PC) is the most frequent pattern of metastasis in patients with locally advanced gastric cancer. Despite this, there is a consensus on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC from gastric cancer. The molecular mechanisms involved in beneficial effects of HIPEC remain unexplored.

Materials and methods: Human gastric cancer MKN45 cells were injected into the peritoneal cavity of immune-deficient NOD-SCID mice. After induction of PC, the animals were randomized into five groups: HIPEC with mitomycin and cisplatin; normothermic intraperitoneal chemotherapy (NIPEC); normothermic intraperitoneal saline; hyperthermic intraperitoneal saline alone; no treatment. After 10 days of treatment, the mice were sacrificed and the extent of PC was assessed.

Results: Compared with the other groups of treatment, HIPEC reduced the extent and severity of peritoneal dissemination as measured by assessing the total number of peritoneal and mesenteric nodules (p<0,05) and the HIPEC procedure increased median survival significantly. By gene array analysis, HIPEC was found to effectively modulate the expression of a subset of genes involved in formation of peritoneal metastasis, including adenomatous polyposis coli; beta (3) subunit of the integrin gene; chemokine stromal cell-derived factor-1 receptor; spleen tyrosine kinase; vascular endothelial growth factor receptor 3; collagen, type IV, alpha 2 and Carbossi-terminal binding proteins 1.

Conclusion: In the present study we have provided evidence that HIPEC protects against peritoneal dissemination in a mouse model of peritoneal gastric carcinogenesis and brings about specific changes in gene expression wich may be related to this protection.