P-selectin, carcinoma metastasis and heparin: novel mechanistic connections with therapeutic implications

Metastasis is a multistep cascade initiated when malignant cells penetrate the tissue surrounding the primary tumor and enter the bloodstream. Classic studies indicated that blood platelets form complexes around tumor cells i n the circulation and facilitate metastases. In other work, the anticoagula nt drug heparin diminished metastasis in murine models, as well is in preli minary human studies. However, attempts to follow up the latter observation using vitamin K antagonists failed, indicating that the primary mechanism of heparin action was unrelated to its anticoagulant properties. Other stud ies showed that the overexpression of sialylated fucosylated glycans in hum an carcinomas is associated with a poor prognosis. We have now brought all these observations together into one mechanistic explanation, which has the rapeutic implications. Carcinoma cells expressing sialylated fucosylated mu cins can interact with platelets, leukocytes and endothelium via the select in family of cell adhesion molecules. The initial organ colonization of int ravenously injected carcinoma cells is attenuated in P-selectin-deficient m ice, in mice receiving tumor cells pretreated with O-sialoglycoprotease (to selectively remove mucins from cell surfaces), or in mice receiving a sing le dose of heparin prior to tumor cell injection. In each case, we found th at formation of a platelet coating on cancer cells was impeded, allowing in creased access of leukocytes to the tumor cells. Several weeks later, all a nimals showed a decrease in the extent of established metastasis, indicatin g a long-lasting effect of the short-term intervention. The absence of obvi ous synergism amongst the three treatments suggests that they all act via a common pathway. Thus, a major mechanism of heparin action in cancer may be inhibition of P-selectin-mediated platelet coating of tumor cells during t he initial phase of the metastatic process. We therefore suggest that hepar in use in cancer be reexplored, specifically during the time interval betwe en initial visualization of a primary tumor until just after definitive sur gical removal.