Pilot Project 5

Hemostasis at the Crossroad of Immunity and Cancer

Project Investigators: Tracy Stokol,  Cynthia Leifer

Additional Collaborators : Nozomi Nishimura, Teresa Southard

Pathologic activation of hemostasis in cancer is associated with systemic thrombotic events and transformation, growth and metastasis of various tumors. Tissue factor (TF), the main activator of coagulation, is overexpressed in breast tumors in situ and in breast cancer cell lines, particularly triple negative cells, and expression in patient tumors is correlated with a poor prognosis. Cancer-associated TF produces coagulation factor complexes that both trigger thrombosis and induce cell signaling via protease-activated receptors (PARs). Tumor-associated TF and PAR signaling promote tumor growth and metastasis. Tissue factor is also expressed by tumor-associated macrophages (TAMs), which are the most common immune cell in tumors. Macrophages are recruited from bone marrow-derived cells and blood monocytes and play key roles in pathologic hemostasis. They not only upregulate procoagulants, like TF, but also express PARs and PARcleaving proteinases. Exposure to cancer cells and the tumor microenvironment induces a pro-tumorigenic, proangiogenic, and immunosuppressive phenotype in TAMs. However, it is unknown whether breast cancer cellgenerated TF-coagulation complexes and PARs regulate macrophage recruitment to tumors or whether they subsequently modulate macrophage behavior in tumors. This is important since macrophage recruitment and regulation contributes to angiogenesis, metastasis and tumor progression. Our global hypothesis is that breast cancer-associated hemostatic components regulate macrophage recruitment and their inflammatory, angiogenic and hemostatic activity. We further propose that TF sets up a microenvironment that selects for aggressive tumor behavior via intratumoral thrombosis and hypoxia and macrophage-mediated signals. If true, this would provide key mechanistic insight into the anti-tumor effect of TF-drug conjugates and anticoagulants in mouse cancer models. Here, we will begin to test this hypothesis with in vitro and in vivo studies in a collaboration between a veterinarian, immunologist and biomedical engineer.