RET Signaling in Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling

Background:

• Large diameter perineural prostate cancer correlates with poor patient outcomes.
• The GDNF/GFRα1/RET pathway is implicated in pro-oncogenic signaling.
• Nerves secrete both GDNF and GFRα1, suggesting a role in the tumor microenvironment.

Purpose of the Study:

• To investigate the role and mechanism of RET signaling in prostate cancer progression.
• To determine the impact of RET signaling on cancer cell proliferation, invasion, and perineural invasion.
• To identify downstream signaling pathways activated by RET in prostate cancer.

Main Methods:

• Assessed expression of RET, GDNF, and GFRα1 in prostate cancer cell lines.
• Determined the effect of RET signaling on proliferation, invasion, and soft agar colony formation.
• Utilized dorsal root ganglion assays and *in vivo* xenografts to study perineural invasion and tumor growth.
• Examined downstream signaling via Western blotting and conducted knockdown studies.

Main Results:

• RET expression was detected in all prostate cancer cell lines; GFRα1 was limited to specific lines.
• All cell lines responded to GDNF plus GFRα1, and nerve-secreted GFRα1 promoted transformation.
• RET knockdown and anti-GFRα1 antibodies inhibited perineural invasion and tumor growth.
• RET signaling activated ERK/AKT pathways and significantly increased p70S6 kinase phosphorylation, crucial for transformed phenotypes.

Conclusions:

• RET signaling drives prostate cancer-associated transformation and perineural invasion, mediated by p70S6 kinase activation.
• Nerve-secreted GFRα1 acts as a limiting factor for RET signaling, establishing a perineural niche conducive to cancer progression.
• Targeting the RET pathway, particularly within the perineural niche, may offer therapeutic strategies for prostate cancer.