Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo.

Abstract

Platelet-adhesive protein-tumor cell interaction was studied in vitro and in vivo. Monoclonal antibody 1OE5, which inhibits binding of fibronectin and von Willebrand factor to the platelet membrane glycoprotein GPIIb-GPIIIa complex, inhibited the binding of mouse CT26 and human HCI8 colon carcinoma cells to platelets by 63-65%, whereas an irrelevant monoclonal antibody, 3B2, had no effect. Monoclonal antibody 6D1, which inhibits binding of von Willebrand factor to GPIb, also had no effect. RGDS, a tetrapeptide that represents the adhesive domain of fibronectin and von Willebrand factor inhibited binding of the tumors to platelets by 64-69%. Monospecific polyclonal antifibronectin antibody inhibited binding by 60-82%; anti-von Willebrand factor antibody inhibited binding by 75-81%.In vivo, polyclonal monospecific anti-mouse von Willebrand factor antibody inhibited pulmonary metastases induced by CT26 tumor cells by 53-64%, B16a amelanotic melanoma cells by 45% and T241 Lewis bladder cells by 46% without induction of thrombocytopenia. Pulmonary metastases with CT26 cells could be inhibited by induction of thrombocytopenia, and reconstituted by infusion of either murine or human platelets. Reconstitution of pulmonary metastases with human platelets could be inhibited 77% by preincubation of human platelets with monoclonal antibody 1OE5 before infusion of platelets into mice.Thus, platelets appear to contribute to metastases by their adhesive interaction with tumor cells via the adhesive proteins fibronectin and von Willebrand factor.

von Willebrand factor expression in osteosarcoma metastasis

“…[16][17][18] Pretreatment of either tumor cells or platelets with an antibody or peptide that neutralizes vWF or blocks vWF-capable receptors (eg integrins GPIIb/ IIIa and GPIb-present on numerous tumor cell lines) has been shown to inhibit tumor cell-platelet interaction in vitro for colon carcinoma, Walker 256 carcinosarcoma, melanoma and osteosarcoma cell lines (including SAOS2). 19,[44][45][46][47][48][49][50][51][52] Notably, treatment with monoclonal anti-vWF antibody significantly decreased tumor cell metastases in vivo for colon, Lewis bladder and melanoma carcinoma cell 53 suggested that this tumor cell-platelet mechanism may be partially responsible for the common metastasis of osteosarcoma to the lung. In support of this, the osteosarcoma cell lines MG63, HOS, U2-OS, TE-85 and SAOS2 have been shown to induce platelet aggregation.…”

“…[16][17][18] The aggregation of tumor cells and platelets may assist in metastasis by producing a mixed platelet-tumor cell mass that supports adherence of tumor cells to the blood vessel wall and protects the tumor cells from destruction by the immune system. [16][17][18][19][20] In this study, we investigated the disposition of vWF in osteosarcoma through the analysis of messenger RNA (mRNA) and protein expression in tumor samples. Our results suggest that inappropriate expression of the vWF gene occurs during the metastatic spread of osteosarcoma.…”

The role of platelet activation in tumor metastasis

“…Platelets adhesion molecules are involved in mediation of platelet-tumor cell interactions. Since GPIIb/IIIa complex was convincingly shown to mediate this process, platelets antagonist based on its inhibition are being tested [5]. The antagonists of GPIIb/IIIa can be divided into RGD-mimicking nanopeptides and monoclonal antibodies binding this complex.…”

“…5,6]. Experimentally induced thrombocytopenia (depletion of platelets) was shown to reduce the development of metastasis both in transplant and syngeneic mouse tumor models [7].…”

Platelet-induced enhancement of LS174T colon carcinoma and THP-1 monocytoid cell adhesion to vascular endothelium under flow

“…Accumulating evidence provides strong support for the concept that platelets facilitate the hematogenous dissemination of tumor cells, the most convincing of which is the inhibition of metastasis by experimental platelet depletion and the reconstitution of metastatic potential after platelet repletion (16,19). It is believed that platelets provide a protective shield against cytotoxic immune cells (32) and facilitate tumor cell extravasation by potentiating tumor cell adhesive interactions with ECM proteins of the vessel wall (9,13).…”