| Tumor-platelet aggregates play an important role in tumor spread. The ability of tumor cells to aggregate platelets, i.e. tumor cell induced platelet aggregation (TCIPA), confers a number of advantages to the survival of tumor cells in the vasculature and to their successful metastasis. Understanding the mechanisms of TCIPA may lead to novel inhibitors of hematogenous metastasis. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play crucial roles in metastasis and platelet aggregation. Additionally, TCIPA and the arrest of tumor containing aggregates depend on platelet surface receptors. Therefore, I have studied the roles of MMP-2 and TIMP-4 in TCIPA using human HT-1080 fibrosarcoma and A549 lung carcinoma cells to induce TCIPA. Furthermore, I have investigated the role of two major platelet receptors: glycoprotein Ib (GPIb) and IIb/IIIa (GPIIb/IIIa) in TCIPA using a novel solid phase agonist, von Willebrand Factor (vWF) immobilized on polystyrene beads. In addition, the role of nitric oxide (NO) and prostacyclin (PGI2) in regulating TCIPA was also studied. It is concluded that (1) human tumor cells aggregate platelets via mechanism(s) that are mediated, in part, by MMP-2, (2) NO inhibits TCIPA by inhibiting the release of MMP-2, (3) these effects of NO are cGMP-dependant, (4) TCIPA results in the expression of platelet GPIIb/IIIa, while decreasing GPIb expression, (5) vWF potentiates TCIPA, (6) these effects of vWF are inhibited by NO and PGI2, (7) NO and PGI2 differentially affect the expression and activation of GPIIb/IIIa, (8) platelet TIMP-4 is not released during TCIPA, and (9) pharmacological recombinant TIMP-4 has the ability to modulate TCIPA. |
