Abstract
Prostate cancer (PCa) is believed to metastasize through the blood/lymphatics systems; however, PCa may utilize the extensive innervation of the prostate for glandular egress. The interaction of PCa and its nerve fibers is observed in 80% of PCa and is termed perineural invasion (PNI). PCa cells have been observed traveling through the endoneurium of nerves, although the underlying mechanisms have not been elucidated. Voltage sensitive sodium channels (VSSC) are multimeric transmembrane protein complexes comprised of a pore-forming α subunit and one or two auxiliary beta (β) subunits with inherent cell adhesion molecule (CAM) functions. The beta-2 isoform (gene SCN2B) interacts with several neural CAMs, while interacting putatively with other prominent neural CAMs. Furthermore, beta-2 exhibits elevated mRNA and protein levels in highly metastatic and castrate-resistant PCa. When overexpressed in weakly aggressive LNCaP cells (2BECFP), beta-2 alters LNCaP cell morphology and enhances LNCaP cell metastasis associated behavior in vitro. We hypothesize that PCa cells use beta-2 as a CAM during PNI and subsequent PCa metastasis. The objective of this study was to determine the effect of beta-2 expression on PCa cell neurotropic metastasis associated behavior. We overexpressed beta-2 as a fusion protein with enhanced cyan fluorescence protein (ECFP) in weakly aggressive LNCaP cells and observed neurotropic effects utilizing our novel ex vivo organotypic spinal cord co-culture model, and performed functional assays with neural matrices and atomic force microscopy. With increased beta-2 expression, PCa cells display a trend of enhanced association with nerve axons. On laminin, a neural CAM, overexpression of beta-2 enhances PCa cell migration, invasion, and growth. 2BECFP cells exhibit marked binding affinity to laminin relative to LNECFP controls, and recombinant beta-2 ectodomain elicits more binding events to laminin than BSA control. Functional overexpression of VSSC beta subunits in PCa may mediate PCa metastatic behavior through association with neural matrices.
Highlights
Prostate Cancer (PCa) is the most highly diagnosed noncutaneous cancer and accounts for the second most cancer deaths among American men [1]
Using beta-2 overexpressing LNCaP cells (2BECFP), vector control LNCaP cells (LNECFP), and highly aggressive C4-2B4 cells, we examined whether the expression of beta-2 altered the neurotropic behavior of PCa cells using a novel ex vivo spinal co-culture system, in vitro functional metastatic assays, and atomic force microscopy
Myelin Protein Zero Like 2 Precursor (MPZL2) is highly expressed in the thymus, it is expressed in the PNS along with Myelin Protein P0 Precursor (MP0), which is a major component of peripheral myelin
Summary
Prostate Cancer (PCa) is the most highly diagnosed noncutaneous cancer and accounts for the second most cancer deaths among American men [1]. In 2014, nearly 233,000 men will be diagnosed with PCa of which nearly 29,500 will succumb to the disease [1]. Detection of localized PCa allows for treatment options that have pushed five year survival rates to nearly 100% [2]. The ‘‘silent’’ nature of PCa allows for PCa to proceed undetected until becoming locally or regionally advanced leading to distal metastatic spread of the disease, whereby the 5-year survival rate drops to below 35% [3,4]. The afferent prostatic blood flow does not account for the specificity of PCa metastatic lesion incidence within the spine as only 5–10% of prostatic blood flow is directed towards the spinal cord [10,11]. We postulate an alternative perineural route of PCa cell prostatic egress
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