Human Cancer Biology Genes Upregulated in Prostate Cancer Reactive Stroma Promote Prostate Cancer Progression In Vivo

Purpose: Marked reactive stroma formation is associated with poor outcome in clinically localized prostate cancer. We have previously identified genes with diverse functions that are upregulated in reactive stroma. This study tests the hypothesis that expression of these genes in stromal cells enhances prostate cancer growth in vivo. Experimental Design: The expression of reactive stroma genes in prostate stromal cell lines was evaluated by reverse transcriptase (RT)-PCR and qRT-PCR. Genes were knocked down using stable expression of short-hairpin RNAs (shRNA) and the impact on tumorigenesis assessed using the differential reactive stroma (DRS) system, in which prostate stromal cell lines are mixed with LNCaP prostate cancer cells and growth as subcutaneous xenografts assessed. Results:Nine of 10 reactive stroma genes testedwere expressed in one ormore prostate stromal cell lines. Gene knockdownof c-Kit,Wnt10B, Bmi1,Gli2, or COMPall resulted in decreased tumorigenesis in theDRS model. In all tumors analyzed, angiogenesis was decreased and there were variable effects on proliferation and apoptosis in the LNCaP cells.Wnt10Bhas been associatedwith stem/progenitor cell phenotype in other tissue types. Using a RT-PCR array, we detected downregulation of multiple genes involved in stem/ progenitor cell biology such as OCT4 and LIF as well as cytokines such as VEGFA, BDNF, and CSF2 in cells with Wnt10B knockdown. Conclusions: These findings show that genes upregulated in prostate cancer–reactive stroma promote progression when expressed in prostate stromal cells. Moreover, these data indicate that the DRS model recapitulates key aspects of cancer cell/reactive stroma interactions in prostate cancer.ClinCancer Res; 20(1);