Hedgehog Pathway Activation Is Associated with VEGF Induction in Prostate Cancer Microenvironment
V Tzelepi, M Karlou, A Hoang, C Logothetis, P Troncoso, E Efstathiou. M.D. Anderson Cancer Center, Houston
Background: Investigators have speculated that prostate cancer progression usurps normal prostate and bone development pathways. Hedgehog (HH) signaling is a stromal-epithelial interacting network central to prostate development and likely implicated in the aggressiveness of prostate cancer (PCa).
Design: A tissue microarray was constructed from prostatectomy specimens from 141 untreated PCa patients (49 with Gleason score ≤6 and 92 ≥7). Non-neoplastic peripheral (PZ) and transition (TZ) zone were also included. Expression of Sonic HH ligand (SHH), Smoothened (SMO), Gli2 and VEGF were evaluated by immunohistochemistry in both epithelium and stroma (cancer associated fibroblasts).
Results: A parallel activation of HH pathway in epithelial and stromal cells, as determined by the correlation of nuclear Gli2 expression (p<0.001 by Pearson's), was noted in PCa and adjacent PZ. Additionally, Gli2 expression was higher in the epithelium and stroma of PZ compared to TZ (p=0.005, p=0.018, respectively). Upstream components SHH, SMO and angiogenic factor VEGF were higher in malignant compared to non-tumor epithelium (p<0.001), whereas expression in the stroma was high in both PCa and PZ. Epithelial VEGF was highly correlated with SHH and SMO expression in the epithelium (p<0.001 and p=0.001, respectively) and stroma (p=0.01, p=0.046, respectively). Moreover, stromal VEGF expression was correlated with stromal SHH, SMO and Gli2 expression (p<0.001, p=0.007, p=0.039, respectively). Finally a parallel downregulation of SHH and VEGF expression was noted in stromal cells of high grade compared to low grade tumors (p=0.004, p<0.001, respectively).
Conclusions: Our findings demonstrate that HH signaling is increased in human PCA microenvironment and adjacent non-tumor areas. These findings are consistent with the view that HH signaling broadly remodels the PCa microenvironment. Increased expression of Gli2 in PZ microenvironment may be related with the susceptibility of this zone to PCa development. The observed co-expression of HH signaling and VEGF suggests that the link between them reported in development may also be implicated in PCa progression. These data suggest that stromal SHH and VEGF expression is implicated in disease aggressiveness, consistent with the view that VEGF and SHH induction is paracrine-mediated early in PCa but autocrine in more advanced settings. These findings, if confirmed, will form the basis for the optimum timing of SHH inhibition and development of combinatorial microenvironment targeting therapies.
Category: Genitourinary (including renal tumors)
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 116, Wednesday Afternoon