Inhibition of Metastases by Anticoagulants

Abstract

Metastasis involves several distinct steps, including one in which the tumor cell, after entry into the bloodstream, comes to rest in a capillary located at the distant site where a metastatic tumor will ultimately form. Components of the blood-clotting pathway may contribute to metastasis by trapping cells in capillaries or by facilitating adherence of cells to capillary walls. Conceivably, anticoagulants could interfere with this step in the metastatic process. In this review, we have summarized current knowledge on the interaction of malignant cells, clotting factors, and anticoagulants. We used computerized (MEDLINE) and manual searches to identify studies done in humans, in animals, and in in vitro systems that were published in English between 1952 and 1998. We found many reports that the formation of metastatic tumors could be inhibited by heparin, a vitamin K antagonist (warfarin), and inhibitors of platelet aggregation (prostacyclin and dipyridamole). Despite these encouraging preliminary results and a compelling biochemical rationale, only limited information exists on the clinical use of anticoagulants for the prevention or treatment of metastatic cancer because there have been so few controlled and prospectively randomized studies on this topic. In view of the preliminary results, anticoagulants may hold promise for the prevention and treatment of metastases. We believe that larger controlled investigations are strongly warranted to evaluate the clinical potential of anticoagulants for the prevention and treatment of metastases in humans.

Prognostic impact of matched preoperative plasma and serum VEGF in patients with primary colorectal carcinoma

“…However, it has recently been shown that isolated platelets from cancer patients contain more VEGF than isolated platelets from healthy controls (Salven et al, 1999b) and a very recent study have demonstrated that the serum VEGF concentrations in cancer patients with normal platelet counts were higher than in healthy controls with normal platelet counts (Lee et al, 2000). Platelet aggregation may contribute to tumour progression by release of a variety of vasoactive and proangiogenic substances in the tumour (Browder et al, 2000) and to metastasis by facilitating adherence of disseminated tumour cells to capillary walls at distant sites (Hejna et al, 1999). Therefore, although the preoperative serum VEGF concentration is affected by in vitro degranulation of platelets, the increased platelet-derived VEGF may influence the biology of a present tumour in vivo, and may presumably reflect tumour burden at the time of surgery.…”

von Willebrand factor expression in osteosarcoma metastasis

“…[11][12][13] Platelet adhesion and aggregation are two processes critical to hematogenous tumor cell metastasis. [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.…”

“…[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.…”

Impaired platelet aggregation in melanoma patients treated with interferon‐α‐2b adjuvant therapy

“…21 Kakkar and Williamson 22,23 and Engelberg 24 noted the antimetastatic effect of heparin and fractionated heparin, and randomized prospective studies currently are in progress. More specifically, in vitro and in vivo murine models have shown that platelet aggregation is one of the mechanisms that promotes metastatic growth by protecting the metastatic tumor cells from natural killer cell cytotoxicity.…”