Semaphorin 4F as a Critical Regulator of Neuro-Epithelial Interactions and a Biomarker of Aggressive Prostate Cancer
Menée sur des lignées cellulaires de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels, via la régulation des interactions entre les nerfs du microenvironnement tumoral et les cellules cancéreuses, la sémaphorine 4F favorise la progression tumorale
BACKGROUND: Semaphorin 4F (S4F) has roles in embryological axon guidance and is expressed in adults. S4F is involved in cancer-induced neurogenesis. METHODS: Prostate cells were transfected with S4F retrovirus. Cells and controls were used for a BrdU incorporation assay (proliferation) and in vitro scratch and matrigel transwell chamber invasion assay (migration). Monoclonal antibodies were developed using baculovirus expressed recombinant GST-S4F and used to immunostain tissue microarrays. Slides were imaged using deconvolution and analyzed using tissue segmentation. Data was correlated with clinico-pathological parameters, other biomarkers and survival analysis performed. Heterogeneity of S4F expression was analyzed with unsupervised clustering algorithms. RESULTS: Proliferation rates measured by BrdU incorporation were higher in all S4F transfected cells. S4F over-expression was associated with increased motility of the cancer cells. S4F expression was over expressed in HGPIN / PCa than normal epithelium. S4F expression correlated with seminal vesicle invasion. Patients with high values of S4F in PCa cytoplasm are at significantly higher risk of biochemical recurrence, by univariate and multivariate analysis. S4F cytoplasmic expression in PCa cells also correlates with nerve density in PCa and perineural invasion diameter. Correlations were identified with NFkB and inversely with apoptosis in PNI. CONCLUSION: This data demonstrates that S4F is significantly involved in human PCa progression. S4F is a key regulator of the interactions between nerves in the tumor microenvironment and cancer cells. Because of the importance of cancer nerve interaction in the biology of cancer and its clinical implication, S4F can be considered a major therapeutic target.