Stem cell factor mediates multiple cellular responses by binding to and activating the receptor tyrosine kinase, c-KIT (CD117). Since its discovery in 1987, c-KIT has been known as an oncogene, and SCF/c-KIT signaling is required for the development of hematopoietic stem cells, melanocytes, and germ cells. In 2012, our team first made a novel discovery that SCF/c-KIT signaling is one of the key drivers of angiogenesis and vascular permeability. Hypoxia stimulates the expression of c-KIT, which in turn enhances the expression of VEGF, IL-8, and cyclin D1, resulting in the increased neovascularization. Besides, the activation of c-KIT signaling induces vascular permeability of endothelial cells, which is critical to the development of edema in patients.
The mechanism of SCF/c-KIT regarding to the mediation of angiogenesis and vascular permeability in response to hypoxia is demystified as below.
To date, VEGF is the only proven retinal disease target. However, we have verified that SCF/c-KIT, independently of VEGF, induces neovascularization and vascular permeability, which are not mediated by anti-VEGF drugs. This finding could be an answer to the reason why up to 40% of patients are refractory to anti-VEGF treatment. For further information about SCF/c-KIT pathway as a novel ophthalmology target, please see our publication here.
In oncology, tumor microenvironment (TME) is a new battlefield for every anti-cancer drugs. TME plays a critical role in multiple aspects of tumorigenesis and therapeutic resistance. TME is characteristically hypoxic, and induces SCF/c-KIT expression. In addition, Mast Cell whose molecular marker is c-KIT molds the TME by recruiting MDSC, TAM, and TAF, making anti-c-KIT an attractive strategy for the tumor immunosuppression. At a molecular level, the mutation or overexpression/ amplification of c-KIT is reported to be widely engaged in the pathogenesis of small cell lung carcinoma, gastrointestinal stromal tumor, leukemia, glioblastoma, ovarian cancer, and systemic mastocytosis.