Port-site metastasis after CO2 pneumoperitoneum: role of adhesion molecules and prevention with antiadhesion molecules.

Abstract

Port-site metastasis is a continuing problem in laparoscopic cancer surgery. To clarify the role of adhesion molecules in the development of port-site metastasis, particularly with regard to prevention, we performed experiments in which port-site metastasis was inhibited using antibodies against extracellular matrix proteins or the active Arg-Gly-Asp (RGD) peptide after CO2 pneumoperitoneum in a murine model. We examined the development of port-site metastasis under the following conditions: (1) CO2 pneumoperitoneum with or without hyaluronic acid and anti-integrin or anti-CD44 antibody and (2) CO2 pneumoperitoneum and a RGD peptide or pseudo-RGD sequence peptide (FC-336). BALB/c mice ( n = 130) were injected with 5 x 10(5) human gastric cancer cells (MKN45) and either antibody or peptide, treated with CO2 pneumoperitoneum, and injected intraperitoneally with antibody or peptide for 5 days. Three weeks after CO2 pneumoperitoneum, the frequency and weight of port-site metastatic tumors were determined. Anti-integrin antibody significantly decreased the weight of port-site metastatic tumors without hyaluronic acid (control vs anti-integrin: 8.2 +/- 7.1 vs 3.6 +/- 4.5 mg; p < 0.05) but not the frequency of port-site metastases. With hyaluronic acid, the frequency of port-site metastasis and the weight of port-site metastatic tumors were significantly decreased both by anti-integrin and by anti-CD44 antibody (control vs anti-integrin and anti-CD44; 95% and 8.5 +/- 7.2 mg vs 50% and 3.1 +/- 4.3 mg and 55% and 3.3 +/- 5.1 mg, respectively; p < 0.05). RGD peptide and FC-336 also inhibited port-site metastasis in a dose-dependent manner. Cell adhesion molecules integrin and CD44 play an important role in the development of port-site metastasis after laparoscopic cancer surgery. Intraperitoneal injection of RGD peptide or pseudo-RGD sequence peptide (FC-336) can prevent port-site metastasis.