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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hirabayashi
Y
Y
Department of Surgery I, Oita Medical University, 1-1 Idaigaoka, 879-5593, Hasama-machi, Oita, Japan.
Yamaguchi
K
K
Shiraishi
N
N
Adachi
Y
Y
Saiki
I
I
Kitano
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D002245:Carbon Dioxide / Q000008:administration & dosage; D002277:Carcinoma / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000502:physiology*; D045744:Cell Line, Tumor / Q000637:transplantation; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D016023:Integrins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009366:Neoplasm Seeding; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011028:Pneumoperitoneum, Artificial / Q000009:adverse effects*; D013274:Stomach Neoplasms / Q000473:pathology; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; C110986:FC 336; D018960:Hyaluronan Receptors; D016023:Integrins; D009842:Oligopeptides; D002245:Carbon Dioxide; C047981:arginyl-glycyl-aspartic acid; D006820:Hyaluronic Acid