Specific cellular and molecular interactions between prostate cancer (PC) cells and the bone microenvironment lead to expansion of the metastatic deposit, disease progression, and ultimately significant morbidity and mortality. We recently reported an association between expression of the tyrosine kinase receptor c-kit and clinical PC progression, with the highest expression seen in clinical metastatic bone specimens. Moreover, we found that intraosseous tumors formed by otherwise c-kit negative PC3 cells injected into human bone xenografts in SCID mice (SCID-hu model) expressed c-kit. To determine the relevance of these findings, we examined additional human PC cell lines, namely LNCaP, C42b, and DU145, for the expression of c-kit in vitro and in vivo. While none of the cultured PC cells expressed c-kit at the message or protein level, immunostaining for c-kit in intraosseous tumors produced by these cells in the SCID-hu model revealed a distinctive and specific reactivity in the cancer cell compartment. The induction of c-kit expression in PC cells growing within the bone microenvironment was emulated by co-culture of PC3 cells and bone-derived cells embedded in Matrigel, as demonstrated by RT-PCR analysis. In an attempt to mimic the de novo c-kit expression observed in the SCID-hu model and to identify potential signaling pathways triggered by c-kit activation by its ligand stem cell factor (SCF), normally expressed by the bone microenvironment, we transiently transfected PC3 cells with wild-type c-kit. Activation of c-kit was confirmed by immunoblotting for phosphorylated c-kit. Using the whole human genome Agilent microarray, we found that 220 genes were differentially expressed when SCF-treated and non-treated c-kit-transfected PC3 cells were compared, resulting in discrete functional sub-networks that were coordinately up or down-regulated. Most notably, pathway and genetic network analysis revealed that c-kit activation resulted in an up-regulated fibroblast growth factor-2-mediated sub-network. Taken together, these results suggest that c-kit induction in PC cells in the bone microenvironment modulates cell-cell interaction pathways and growth factor signaling systems that ultimately lead to expansion of bone metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1439.