Tissue Factor in Wet Age-Related Macular Degeneration
Tissue Factor (TF) may play a particularly important role in the pathogenesis of AMD. The intracellular signaling pathways driven by TF promote inflammation and angiogenesis, key drivers of the retinal injury and vision impairment that characterize neovascular or “wet” AMD. Under normal conditions, retinal endothelial and smooth muscle cells do not express TF. By contrast, TF is dramatically increased in the retinal tissues of patients with AMD and proliferative diabetic retinopathy.
In addition, the positive feedback loop between TF and cytokines that regulate blood vessel growth and inflammation in AMD supports the potential of TF as a therapeutic target for choroidal neovascularization, or CNV, the pathophysiological hallmark of wet AMD.
Selective targeting of aberrant TF in the retina offers a potential two-fold advantage for the treatment of AMD. First, because TF is considerably and selectively overexpressed in the vasculature of AMD blood vessels compared to normal choroid, there is a reduced potential for off-target side effects. Second, in contrast with the anti-VEGF agents that are currently used for the treatment of AMD, this novel selective anti-TF therapy has the potential to bind to and cause removal of existing pathologic neovascularization, providing a disease-modifying approach to wet AMD.
Tissue Factor in Cancer
TF is thought to play a role in many aspects of cancer biology including thrombosis, metastasis, tumor growth, and tumor angiogenesis. In fact, TF is expressed in a wide variety of cancers such as melanoma, ovarian, pancreatic and prostate cancer and such expression has been shown to be an independent predictor of cancer progression, more advanced stage, higher metastatic rates, and poor survival. Furthermore, TF has also been suggested to play a role in the increased rate of deep vein thrombosis and other problems related to hypercoagulability that can occur in cancer patients.
TF is expressed not only by tumor cells themselves, but also by vascular, stromal and inflammatory cells in the tumor microenvironment. Thus, an anti-TF agent could have the effect of addressing both the tumor and its supportive microenvironment simultaneously.
Together, this growing body of evidence suggests that inhibition of TF could reduce the activity of several pathologic pathways known to increase tumor growth, vascularization, and metastasis and underscores the potential for targeting TF in cancer.