Inhibition of tumor implantation at sites of trauma by Arg-Gly-Asp containing proteins and peptides

Abstract

We report on the inhibition of wound implantation by TA3Ha mammary carcinoma cells by Arg-Gly-Asp containing proteins and peptides using a hepatic wedge resection model. Intravenously injected TA3Ha cells rarely form tumor in the liver of syngeneic mice, but after hepatic wedge resection, 45% (107/240) of the mice develop tumors in the hepatic wound. Hepatic wound implantation is significantly (P = 0.01) inhibited by pretreating the cells with whole mouse plasma, but not with fibrinogen-depleted plasma or serum. Tumor inhibition is also achieved by pretreatment of cells with fibrinogen (P = 0.05-0.0004), fibronectin (P = 0.007) and laminin, but not by albumin. The active domain appears to be the RGDS sequence since the deca- and tetrapeptides containing RGDS inhibit wound implantation (P less than 0.05). However, the tetrapeptide Arg-Gly-Glu-Ser has no such activity. None of these agents affects ascites tumor formation by the intraperitoneally injected cells, suggesting that anchorage independent growth of cells is not affected. We propose that proteins and peptides containing RGD occupy the binding sites and prevent the cells from interacting with cell adhesion proteins in healing wounds. Proteins and/or peptides containing RGD may be useful for preventing local recurrence in postsurgical cancer patients.

The potential role of integrin receptor subunits in the formation of local recurrence and distant metastasis by mouse breast cancer cells

“…The tumor inhibition results seen in this study are comparable to those found in the case of TA3Ha implantation at surgically induced liver wounds [30,31]. Thus, it is likely that the TA3Ha cells use similar mechanisms to implant at surgical sites in different organs.…”

Growth and metastasis of human breast cancers in athymic nude mice

“…Furthermore, we noted that tumor cell implantation at surgical sites in different organs is critically dependent upon tumor interaction with the RGDS containing extracellular matrix at the wound site [27,28,30]. In the TA3Ha mouse tumor model, tumor implantation was maximal in the early phases of wound healing without regard to the organ injured.…”

“…For example, pretreatment of tumor cells with fibronectin, fibrinogen, laminin or peptides containing Arg-Gly-Asp (RGD) residues but not albumin or Arg-Gly-Glu (RGE) peptides prevents tumor implantation and growth at wound sites [27,30]. For example, pretreatment of tumor cells with fibronectin, fibrinogen, laminin or peptides containing Arg-Gly-Asp (RGD) residues but not albumin or Arg-Gly-Glu (RGE) peptides prevents tumor implantation and growth at wound sites [27,30].…”

The role of fibronectin in tumor implantation at surgical sites

“…The inhibitory effects were seen to a similar extent with all four different fibronectins used, suggesting that for the experimental manipulation of implantation, the species of origin, or the source of fibronectin is of little relevance. In an earlier study, we found that proteins and peptides containing RGDS residues prevented tumor implantation in hepatic wound sites [53]. In contrast, neither albumin nor RGDS peptide had such an effect.…”