73P - Preclinical and clinical presentation of the nerve-driven tumor spread

Background

Tumor infiltration by nerves and axial bone metastases often occur in prostate cancer (PCa) patients, however the mechanisms and the link between these processes are not well understood. Here, we report a PCa mouse model, which recapitulates this cancer route of spreading and correlates with radiological images from PCa patients.

Methods

The human androgen-independent PC3-ML cell line with reported bone metastasis potential was orthotopically injected into the prostate of SCID/Bg mice to observe the natural history of cancer spread instead of commonly used intratibial or intracardiac injections. The process of primary and secondary tumor development was monitored by magnetic resonance imaging (MRI). The tissues were collected and immunostained for neuronal markers, neurofilament (NF), and tyrosine hydroxylase (TH), as well as prostate cancer cell marker, pan-cytokeratin, and a vascular marker, CD31. Additionally, clinical cases of patients with representative MRI images of bone metastases and PNI were selected.

Results

The mice MRI revealed the presence of primary prostate tumor with secondary tumors located mostly along the lumbar spinal cord and pelvis, which led to secondary bone infiltration. The histopathological analysis confirmed the presence of PCa cells along the spine with its infiltration. The PCa cells created clusters, which spread along the small, NF-positive nerve fibers that were directed into the bone area. We ruled out the retrograde vessel infiltration by CD31 immunostaining. The clinical relevance of our model was confirmed by the radiological presentation of human PCa cases: 1) a patient with castration-sensitive PCa, with oligometastatic disease (one sacrum metastasis) and infiltration of neurovascular bundle; 2) a patient with castration-resistant PCa with PNI and a relapse in the ilium, who subsequently developed perispinal metastases along the lumbar plexus and spine.

Conclusions

Altogether, the results of our study suggest that PNI may be responsible for the initial PCa dissemination to bone. MRI imaging has adequate sensitivity to detect the nerve infiltration, however it is not commonly used in disseminated PCa patients. Consequently, the number of cases with spine infiltration and bone metastases may be underreported.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Georgetown University Medical Center.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.