SiRNA-mediated reduction of alpha-actinin-1 inhibits pressure-induced murine tumor cell wound implantation and enhances tumor-free survival.
Viable cancer cells can commonly be recovered from surgical sites and venous blood during tumor resection. The adhesion of these cells to surrounding tissues may impact patient outcomes. Iatrogenic exposure to increased extracellular pressure modulates integrin binding affinity and stimulates colon cancer cell adhesion in vitro through an alpha-actinin-1-dependent signaling pathway. We hypothesized that preoperative small interfering RNA-mediated silencing of alpha-actinin-1 in tumor tissue could disrupt pressure-stimulated cancer cell adhesion to murine surgical wounds and thereby enhance subsequent tumor-free survival. Reducing alpha-actinin-1 in CT26 murine adenocarcinoma cells blocked cell adhesion to collagen in vitro and similarly inhibited pressure-induced CT26 implantation in murine surgical wounds in vivo. Surgical wound contamination with pressure-activated CT26 cells significantly reduced tumor-free survival compared to contamination with tumor cells maintained under ambient pressure. However, mice treated with pressure-activated CT26 cells preoperatively transfected with alpha-actinin-1-specific small interfering RNA displayed reduced surgical site implantation and increased tumor-free survival compared to mice exposed to pressure-activated cells expressing normal levels of alpha-actinin-1 protein. These results suggest that pressure activation of malignant cells promotes tumor development and impairs tumor-free survival. alpha-Actinin-1 may be an effective therapeutic target to inhibit perioperative pressure-stimulated tumor cell implantation.
Craig
David H
DH
Department of Surgery, John D. Dingell VA Medical Center and Wayne State University, Detroit, MI 48201, USA.
Downey
Christina
C
Basson
Marc D
MD
D000185:Actinin / Q000032:analysis* / Q000235:genetics; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D007049:Iatrogenic Disease / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000473:pathology* / Q000601:surgery; D009360:Neoplastic Cells, Circulating / Q000187:drug effects* / Q000473:pathology; D011183:Postoperative Complications / Q000517:prevention & control*; D011300:Preoperative Care; D034741:RNA, Small Interfering / Q000008:administration & dosage*
C528567:Actn1 protein, mouse; D034741:RNA, Small Interfering; D000185:Actinin