# The contributions of sensory nerves to bone metastasis and associated bone pain

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $376,478

## Abstract

Project Summary
Bone metastasis remains a major cause of death among patients with prostate cancer. Unfortunately, current
treatments for bone metastases are mainly palliative. A major complication of bone metastasis is bone pain.
Although several lines of study have suggested that nerves have a role in cancer progression, and that bone
pain and overall survival are negatively correlated, the mechanisms involved remain elusive. We have found
that: 1) cancer metastasis to bone or metastatic bone disease enriches sensory nerves that express the
neuropeptide calcitonin gene-related peptide (CGRP) in the bone, and that causes bone pain; 2) bone-metastatic
cancer cells express elevated levels of calcitonin-receptor like receptor (CRLR); 3) CGRP induces cancer
proliferation through the CRLR/p38 pathway; 4) activated FMS-like tyrosine kinase 3 receptor (Flt3) is present
in the dorsal root ganglia of mice presenting bone pain indicators; 5) bone-metastatic cancer cells express
elevated levels of the Flt3 ligand (FL); and 6) FL induces the sprouting of sensory nerves. We therefore
hypothesize that (a) FL derived from bone-metastatic prostate cancer stimulates sensory nerves through Flt3,
resulting in cancer-induced bone pain; and (b) CGRP expressed by cancer-associated sensory nerves induces
progression of metastatic bone disease through the CRLR/p38 pathway. In this R01 proposal, submitted in
response to PAR-16-245, we will: (1) Determine whether bone-metastatic cancer cells increase sensory nerve
sprouting and CGRP synthesis in sensory nerves, contributing to cancer-induced bone pain, through the FL/Flt3
axis; and (2) Determine whether CGRP expressed by sensory nerves in bone-metastatic lesions stimulate bone
metastatic outgrowth through CRLR/p38. Using an in vitro primary dorsal root ganglia culture system and a
unique mouse model of cancer-induced bone pain, will allow us to measure within the same animal: (i) tumor
growth, (ii) skeletal innervation, (iii) bone remodeling, and (iv) resultant pain behaviors. Using bone biopsies from
patients, we will probe the molecular mechanisms whereby the crosstalk between bone metastatic cancer and
sensory nerves controls both progression of bone metastases and development of associated pain. We will use
these results to develop a new therapeutic strategy targeting cancer/nerve interactions. In the short term, this
study will elucidate new mechanisms of bone metastasis and cancer-induced bone pain. In the long run, a better
understanding of how metastatic progression and pain signals influence one another to worsen disease
progression will aid in discovering new therapeutic targets for both cancer-induced bone pain and bone
metastatic cancer – areas in which current therapies are wanting – to decrease suffering and improve the survival
of cancer patients with bone metastases.

## Key facts

- **NIH application ID:** 10120655
- **Project number:** 5R01CA238888-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Yusuke Shiozawa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,478
- **Award type:** 5
- **Project period:** 2020-03-05 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120655

## Citation

> US National Institutes of Health, RePORTER application 10120655, The contributions of sensory nerves to bone metastasis and associated bone pain (5R01CA238888-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120655. Licensed CC0.

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