Biologic correlates and significance of axonogenesis in prostate cancer

Abstract

Cancer related axonogenesis and neurogenesis are recently described biologic phenomena. Our previously published data showed that nerve density and the number of neurons in the parasympathetic ganglia are increased in prostate cancer and associated with aggressive disease. Tissue microarrays were constructed from 640 radical prostatectomy specimens with prostate cancer. Anti-PGP 9.5 antibodies were used to identify and quantify nerve density. Protein expression was objectively analyzed using deconvolution imaging, image segmentation and image analysis. Data was correlated with clinico-pathological variables and tissue biomarkers available in our database. Nerve density, as measured by PGP 9.5 expression, had a weak but significant positive correlation with the lymph node status (rho=0.106; p=0.0275). By Cox univariate analysis, PGP 9.5 was a predictor of time to biochemical recurrence, but not on multivariate analysis. Increased nerve density correlated with increased proliferation of prostate cancer cells. It also correlated with expression of proteins involved in survival pathways (p-Akt, NFKB, GSK-2, PIM-2, CMYC, SKP-2, SRF, P27n, PTEN), with increased levels of hormonal regulation elements (AR, ER Alpha), and co-regulators and repressors (SRC-1, SRC-2, AIB-1, DAX). Axonogenesis is a recently described phenomenon of paramount importance in the biology of prostate cancer. While the degree of axonogenesis is predictive of aggressive behavior in prostate cancer, it does not add to the information present in current models on multivariate analysis. We present data that corroborates that axonogenesis is involved in biological processes such as proliferation of prostate cancer, through activation of survival pathways and interaction with hormonal regulation.

Role of tumor microenvironment in tumorigenesis

“…Many markers have gradually been found to be expressed in a large number of prostatic NE cancer cases227, such as K18 and K8 cytokeratins 228, α-methylacyl-CoA-racemase (AMACR) 228, plasma anterior gradient 2 (AGR2) 229, and PGP9.5 230. Additionally, neuron-specific enolase (NSE) and chromogranin A (CgA) may be the most frequently expressed neuropeptides 231-233, but they also have limitations in sensitivity, specificity, reproducibility, etc.…”

Neuronal Activity in Ontogeny and Oncology

“…Prostate cancer-induced axonogenesis has since been demonstrated in vivo [185], and, as discussed below, has also been described in other malignancies such as pancreatic cancer. Nerve density correlates with prostate cancer cell proliferation and with the expression of proteins involved in survival and hormonal regulation pathways in human radical prostatectomy specimens [186]. Another group has shown that proNGF (precursor to nerve growth factor and known to induce axonogenesis) was overexpressed in prostate cancer specimens in comparison to BPH samples.…”

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8+ tumor‐associated lymphocytes and poor prognosis in prostate cancer

“…Since tumor‐infiltrating neural fibers are a common feature of TME and play an important role in prostate tumor growth and progression, we used the PGP9.5 to label the nerves and neurons as well. Although PGP9.5 is not entirely specific for nerve tissue, it is a suitable and sensitive neural marker for detection of nerves in prostate cancer in conjunction with morphological confirmation …”