Abstract LB-315: CD117 tyrosine kinase activation drives prostate cancer aggressiveness

Abstract

Abstract Tyrosine kinase receptors drive prostate cancer progression and metastasis. In particular, CD117/c-kit expression is upregulated during tumor progression with the highest levels being expressed in bone metastases. In addition, the numbers of circulating CD117+ tumor cells were higher in advanced prostate cancer patients. The presence of these cells in patients' circulation after radical prostatectomy was also associated with biochemical recurrence. Further, the expression of CD117 can be upregulated on prostate cancer cells after repeated culturing in the bone microenvironment. These data indicated that CD117 expression and activation may be associated with prostate cancer aggressiveness. LNCaP-C4-2 cells were sorted into CD117+ and negative cell populations. Proliferation, matrigel invasion, sphere formation, and gene expression were compared in the two cell populations in the presence and absence of the ligand stem cell factor (SCF) or CD117 and Akt inhibitors. To track cells during coculture and competition experiments, sorted cells were infected to express mCherry (CD117+) or ZsGreen (negative). Using these cells, competition was tracked using an IncuCyte ZOOM live cell imager for in vitro studies and an IVIS imager for in vivo xenograft tumor initiation studies. To better visualize transendothelial migration, a 3D microfluidic metastasis-on-a-chip was developed to track tumor cell migration through the ECM and across an endothelial cell layer. Here, we examine the activation of CD117 in prostate cancer cell progression and migration. CD117 expression was associated with increased proliferation, migration, and EMT marker expression. Interestingly, treatment with the CD117 ligand stem cell factor (SCF) reduced proliferation but further enhanced invasion indicating that CD117 activation may drive metastasis. CD117 activation stimulated Akt expression and drove the cancer stem cell phenotype as demonstrated by increased Oct4 and Sox2 expression. CD117 expression was associated with increased expression of cancer progression and EMT signaling pathways. Using live cell imaging, competition between CD117+ and negative cells was visualized in proliferation, scratch healing, invasion, trans-endothelial migration, and sphere formation. Xenograft models also demonstrated competition in vivo with CD117 expression increasing tumor initiation. Intravital imaging and sectioning of tumors demonstrated the localization and composition of co-injected cells. Using 3D microfluidics, we have modeled the competition between CD117+ and negative cell populations during transendothelial migration. CD117 expression on prostate cancer cells drives a more aggressive cell phenotype and may be involved in metastasis. Further, CD117+ cells represent a possible cancer stem cell population. Citation Format: Lihong Shi, Koran Harris, Brittni Foster, Aleksander Skardal, Bethany Kerr. CD117 tyrosine kinase activation drives prostate cancer aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-315.