Biologic Significance of Axonogenesis in Prostate Cancer Measured by PGP 9.5.
Adriana Olar, Rile Li, Dandan He, Diego Florentin, Gustavo Ayala. Baylor College of Medicine, Houston, TX
Background: Cancer related axonogenesis (increase in nerve density) and neurogenesis (increased number of ganglion cell bodies) is a recently described biologic phenomenon. Our previously published data showed that nerve density in prostate cancer (PCa) and the number of neurons in the parasympathetic ganglia are increased with prostate cancer (PCa) progression. Protein gene product 9.5 (PGP 9.5) is a member of the ubiquitin hydrolase family of proteins, confined to the cytoplasm of the nerves and neurons. It is a cytoplasmic neuron-specific protein structurally and immunologically distinct from neuron-specific enolase.
Design: Tissue microarrays were constructed from 435 radical prostatectomy specimens with PCa. Anti-PGP 9.5 antibodies were used to identify and quantify nerve density. Protein expression was objectively analyzed using image deconvolution, segmentation and computerized digital image analysis. Data was correlated with clinico-pathological variables and tissue biomarkers available in our database.
Results: Of all of the analyzed clinico-pathological parameters, only the lymph node status had a weak but significant positive correlation with nerve density as measured by PGP 9.5 expression (rho=0.106; p=0.0275). By Cox univariate analysis, PGP 9.5 was a predictor of time to biochemical recurrence (p=0.05). However, it was not an independent predictor of biochemical recurrence on multivariate analysis. Increased nerve density correlated with increased proliferation of PCa cells, highlighted by Ki67 (rho=0.186, p=0.0019). It also correlated positively with expression of proteins involved in survival pathways such as pAKT (rho=0.191, p=0.0015), pNFKB p536 (rho=0.217, p=0.0060), GSK2 (rho=0.152, p=0.0131), PIM2 (rho=0.198, p=0.0017), CMYC (rho=0.134, p=0.0463), SKP2 (rho=0.157, p=0.0029), SRF (rho=0.320, p=0.0000), P27 (rho=0.197, p=0.0007), and negatively with PTEN (rho=-0.178, p=0.0356). Increased nerve density correlated with increased levels of hormonal regulation elements: AR (rho=0.148, p=0.0100), ER Alpha (rho=0.296, p=0.0409); and with co-regulators and repressors: SRC1 (rho=0.164, p=0.0060), TIF2 (rho=0.164, p=0.0064), AIB-1 (rho=-0.399, p=0.0392), DAX (rho=0.163, p=0.0050).
Conclusions: Increase in nerve density or axonogenesis is a recently described phenomenon of paramount importance in the biology of prostate cancer. It is implicated in the regulation of different cancer signaling pathways and is associated with high proliferation rate prostate cancer and decreased survival.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 1:00 PM
Poster Session II # 137, Monday Afternoon