Abstract
Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our 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 show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with 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.
Highlights
Prostate cancer is the second leading cause of cancer mortality in American men, with an estimated 191,930 new cases in 2020
While multiple markers were proposed for prostate cancer C TCs7, most have yet to be validated in the circulation of patients. It remains unproven whether Circulating tumor cells (CTCs) can initiate metastases, which is partially due to an inability to examine the journey of CTCs from the primary tumor to the metastatic n iche[8]
We identified CD117/ c-kit positive CTCs in prostate cancer patients that were associated with cancer severity and biochemical recurrence[19]
Summary
Prostate cancer is the second leading cause of cancer mortality in American men, with an estimated 191,930 new cases in 2020. The first steps of the metastatic process: epithelial-mesenchymal transition (EMT), local invasion, intravasation, and survival in the circulation, represent early targets for identifying patients with aggressive tumors[2,3,4] Cancer cells completing these steps become circulating tumor cells. CD117 is a member of the type III tyrosine kinase receptors which play a key role in cell signaling and are responsible for maintaining cell functions such as cell survival, metabolism, cell growth and progression, proliferation, apoptosis, cell migration, and cell d ifferentiation[21,24,25,26] These effects of CD117 activation and signaling support its potential role in prostate cancer progression and CSC maintenance. Using live-cell imaging and xenograft models, we determine that CD117 activation drives progression, stemness, migration, and TKI resistance
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