Oncogene-Directed Therapies as Modulators of Cancer Coagulopathy, Angiogenesis and Tumor-Vascular Interface

Janusz      Rak; Chloe      Milsom; Linda      May; Joanne      Yu

Abstract

Oncogenic lesions in the cancer cell genome not only alter the intrinsic properties of cancer cells themselves, but also trigger signaling events, the effects of which impact the relationship between tumors and their surrounding host tissues, including the vascular system. Manifestations of the latter include the onset and progression of tumor angiogenesis, and systemic activation of the hemostatic system, a process also known as cancer coagulopathy, or Trousseau syndrome. Indeed, tumor growth, invasion and metastasis are profoundly affected by the properties of the tumor - vascular interface. We postulated earlier that the link between the expression of cancercausing signaling alterations and cancer coagulopathy is at least twofold. First, cancer coagulopathy may emerge indirectly, as an unspecific consequence of vascular permeability and other features of tumor-associated vascular growth, including the pro- and anticoagulant actions of certain angiogenic mediators, some of which (e.g. VEGF) are direct regulatory targets of oncogenes and tumor suppressors. Second, activated oncogenes (K-ras, EGFR or PML-RARα, MET), and/or inactivation of tumor suppressors (e.g. p53 or PTEN) may deregulate some of the hemostatic proteins more directly, i.e. through changes in expression of tissue factor (TF), plasminogen activation inhibitor 1 (PAI-1) and cyclooxygenase 2 (COX-2) [1-4]. In addition to TF expression and release as plasma microvesieles, mutant K-ras may also upregulate expression of thrombin receptors (PAR-1) by cancer cells, thereby possibly rendering such cells hypersensitive to signals emanating from the hemostatic system (e.g. pericellular thrombin). Here, we present an argument that anti-cancer signal transduction inhibitors, also known as ‘targeted agents’ (e.g. Gleevec, Iressa, Erbitux, ATRA) could modulate various vascular processes in cancer, including angiogenesis and cancer coagulopathy, i.e. act as cancer - specific indirect antiangiogenic agents, possibly with a distinct element of anticoagulant activity.

Keywords: Tissue factor, cancer, oncogenes, tumor suppressors, angiogenesis