Letter | Published:

Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection

Nature volume 501, pages 107111 (05 September 2013) | Download Citation

Abstract

Cancer research has been rightly and successfully focused on prevention, early detection, and identification of specific molecular targets that distinguish the malignant cells from the neighbouring benign cells1. However, reducing lethal tissue injury caused by intensive chemoradiotherapy during treatment of late-stage metastatic cancers remains a key clinical challenge. Here we tested whether the induction of adult stem cells could repair chemoradiation-induced tissue injury and prolong overall survival in mice. We found that intestinal stem cells (ISCs)2 expressed Slit2 and its single-span transmembrane cell-surface receptor roundabout 1 (Robo1)3,4. Partial genetic deletion of Robo1 decreased ISC numbers and caused villus hypotrophy, whereas a Slit2 transgene increased ISC numbers and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin 1 (Rspo1; a Wnt agonist)5,6,7,8,9,10,11,12,13,14 plus Slit2 reduced ISC loss, mitigated gut impairment and protected animals from death, without concomitantly decreasing tumour sensitivity to chemotherapy. Therefore Rspo1 and Slit2 may act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.

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Acknowledgements

We thank L. Ma for generating recombinant proteins, M. H. Geng for technical assistance, X. Yang for helping with the in situ hybridization and J. Connett for critical reading of the manuscript. This work was supported by a grant from the National Institutes of Health (CA126897 to J.-G.G.).

Author information

Affiliations

  1. Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA

    • Wei-Jie Zhou
    • , Zhen H. Geng
    •  & Jian-Guo Geng
  2. Departments of Cell and Developmental Biology and Internal Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA

    • Jason R. Spence

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Contributions

W.-J.Z. and Z.H.G. carried out all experiments, collected and analysed data; J.R.S. contributed in vitro intestinal crypt culture; and J.-G.G. proposed the hypothesis, designed experiments and wrote the manuscript.

Competing interests

A patent application has been filed on the basis of this discovery by The Office of Technology Transfer at The University of Michigan.

Corresponding author

Correspondence to Jian-Guo Geng.

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DOI

https://doi.org/10.1038/nature12416

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