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ResearchIn-Press PreviewNeuroscienceOncology Open Access | 10.1172/jci.insight.191905

The contribution of stem cell factor and its receptor c-Kit to cancer-induced bone pain

Kelly F. Contino,1 Jenna Ollodart,1 Yang Yu,1 Sun H. Park,1 Shunsuke Tsuzuki,1 Kara Rollins,1 Tyler M. Heethouse,1 Joshua Chu,1 Laiton R. Steele,1 Takahiro Kimura,2 Jingyun Lee,3 Cristina M. Furdui,3 Lance D. Miller,1 Fang-Chi Hsu,4 and Yusuke Shiozawa1

1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

Find articles by Kimura, T. in: PubMed | Google Scholar |

1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

Find articles by Lee, J. in: PubMed | Google Scholar

1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

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1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

Find articles by Miller, L. in: PubMed | Google Scholar

1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

Find articles by Hsu, F. in: PubMed | Google Scholar

1Department of Cancer Biology and Atrium Health Wake Forest Baptist Comprehe, Wake Forest University School of Medicine, Winston-Salem, United States of America

2Department of Urology, Jikei University School of Medicine, Tokyo, Japan

3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States of America

4Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, United States of America

Find articles by Shiozawa, Y. in: PubMed | Google Scholar |

Published May 5, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.191905.
Copyright © 2026, Contino et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 5, 2026 - Version history
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Abstract

Cancer-induced bone pain (CIBP) is among the most common and debilitating symptoms in patients with bone metastasis. Current treatments are somewhat effective but have severe side effects. For the future development of safer CIBP treatment, in this study, we sought to investigate the mechanisms whereby the cancer/nerve interaction controls CIBP. We found that c-Kit, a receptor tyrosine kinase, was activated in the dorsal root ganglia (DRG) sensory neurons of mice with CIBP and that c-Kit’s sole ligand, stem cell factor (SCF), was enhanced in the bone marrow with bone metastasis. When DRGs were treated SCF or conditioned medium from high SCF-expressing cancer cells, in vitro nerve sprouting was enhanced, and this effect was abolished with c-Kit inhibitors. Mice, intrafemorally inoculated with cancer cells that had varying SCF-expression developed CIBP and enhanced peripheral nerve sprouting in an SCF-dependent manner. Downstream proteomic analysis revealed that SCF upregulated and activated fibroblast growth factor 1 (FGF1) in DRGs. When FGF1 was knocked down in DRGs, SCF-mediated nerve sprouting was prevented. Taken together, our studies demonstrate the importance of the SCF/c-Kit axis in CIBP and nerve sprouting, and identify the SCF/c-Kit/FGF1 pathway as a potential therapeutic target for CIBP.

Graphical Abstract
graphical abstract
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