Semaphorin 4F Expression and Its Role in Axonogenesis and Aggressive Behavior of Prostate Cancer.
Adriana Olar, Rile Le, Yi Ding, Dandan He, Diego Florentin, Gustavo Ayala. Baylor College of Medicine, Houston, TX
Background: Cancer related axono-neurogenesis is a recently described biologic phenomenon. Semaphorin 4F (S4F) is a member of a family of proteins with roles in embryological axon guidance and continues to be expressed in adulthood. S4F produced by prostate cancer (PCa) cells is a key regulator of the interactions between nerves in the tumor microenvironment and cancer cells. S4F is also expressed in the reactive stroma.
Design: Tissue microarrays from 350 radical prostatectomy specimens with PCa were immunostained with antibodies against S4F developed at our institution. Slides were digitized using image deconvolution imaging and analyzed using image segmentation technology. Data was provided on a cell per cell basis (nuclear vs. cytoplasmic), per tumor compartment, per patient. Data was correlated with pertinent clinico-pathological parameters and biomarkers. Survival analysis was performed. To understand the heterogeneity of S4F expression we used an unsupervised clustering algorithm. Each patient was represented to a row, and the expression bins were columns. Color-coding showed the percentage of cells present in each expression bin, with blue representing low % and orange high % of expressing cells.
Results: S4F expression was found in the cytoplasm and nuclei of epithelial PCa and reactive stromal cells and was increased in high grade preneoplastic lesions and PCa compared to normal epithelium. Nuclear and cytoplasmic PCa, as well as stromal S4F expression had different patterns of heterogeneity. Patients with high values of S4F in PCa cytoplasm were at significantly higher risk of biochemical recurrence, by univariate and multivariate analysis [p=0.0007, HR=7.551 (2.34-24.31)]. It was also significant for time to PCa specific death on univariate analysis. S4F cytoplasmic expression in PCa cells also correlated with nerve density in PCa (p=0.04) and perineural invasion diameter (p=0.004), corroborating evidence of S4F's involvement in PCa induced axonogenesis and perineural invasion. Significant correlations were identified with NFkB and inversely with PCa apoptosis in perineural invasion.
Conclusions: By using state of the art quantitative methods we studied S4F biomarker expression within the cancer compartments as well as within the reactive prostatic stroma. Our cumulated data demonstrates that S4F is significantly involved in human PCa progression and regulates the interaction between cancer and nerves.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 1:00 PM
Poster Session II # 136, Monday Afternoon