CTC Marker CD117/c-kit Represents a Prostate Cancer Stem-Like Subpopulation Driving Progression, Migration, and TKI Resistance

Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence. CSCs may also represent a subset of tumor-initiating cells, tumor progenitor cells, disseminated tumor cells, or circulating tumor cells (CTCs); however, which of these aggressive cell populations are also CSCs remains to be determined. In a prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we use LNCaP-C4-2 human prostate cancer cells, which contain a CD117+ subpopulation, to determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness. CD117+ cells displayed increased proliferation and migration. Further, the CD117+ cells represented a CSC population based on stemness marker gene expression and serial tumor initiation studies. SCF activation of CD117 stimulated increased proliferation and invasiveness, while CD117 inhibition by tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.