Role of the tissue factor pathway in the biology of tumor initiating cells 1 [1] Delphine Garnier and Chloe Milsom equally contributed as first authors.

Abstract: Oncogenic transformation and aberrant cellular differentiation are regarded as key processes leading to malignancy. They produce heterogenous cellular populations including subsets of tumour initiating cells (TICs), also known as cancer stem cells (CSCs). Intracellular events involved in these changes profoundly impact the extracellular and systemic constituents of cancer progression, including those dependent on the vascular system. This includes angiogenesis, vasculogenesis, activation of the coagulation system and formation of CSC-related and premetastatic niches. Tissue factor (TF) is a unique cell-associated receptor for coagulation factor VIIa, initiator of blood coagulation, and mediator of cellular signalling, all of which influence vascular homeostasis. Our studies established a link between oncogenic events, angiogenesis and the elevated expression of TF in several types of cancer cells. The latter suggests that cancer coagulopathy and cellular events attributed to the coagulation system may have cancer-specific and genetic causes. Indeed, in human glioma cells, a transforming mutant of the epidermal growth factor receptor (EGFRvIII) triggers not only the expression of TF, but also of its ligand (factor VII) and protease activated receptors (PAR-1 and PAR-2). Consequently, tumour cells expressing EGFRvIII become hypersensitive to contact with blood borne proteases (VIIa, thrombin), which upregulate their production of angiogenic factors (VEGF and IL-8), and contribute to formation of the growth promoting microenvironment (niche). Moreover, TF overexpression accompanies features of cellular aggressiveness such as markers of CSCs (CD133), epithelial-to-mesenchymal transition (EMT) and expression of the angiogenic and prometastatic phenotype. Conversely, TF blocking antibodies inhibit tumour growth, angiogenesis, and especially tumour initiation upon injection of threshold numbers of tumourigenic cells. Likewise, TF depletion in the host compartment (e.g. in low-TF mice) perturbs tumour initiation. These observations suggest that both cancer cells and their adjacent host stroma contribute TF activity to the tumour microenvironment. We postulate that the TF pathway may play an important role in formation of the vascular niche for tumour initiating CSCs, through its procoagulant and signalling effects. Therapeutic blockade of these mechanisms could hamper tumour initiation processes, which are dependent on CSCs and participate in tumour onset, recurrence, drug resistance and metastasis. [Copyright &y& Elsevier]