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

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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Figure 1: Expression of Slit2 and Robo1 in the mouse small intestine.
Figure 2: Phenotypic aberration in Robo1/2 small intestine.
Figure 3: Slit2 transgene enhances small intestinal regeneration.
Figure 4: Slit2 and Rspo1 cooperatively induce ISCs, reduce intestinal damage and prolong overall survival.

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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.).

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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.

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Correspondence to Jian-Guo Geng.

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

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Zhou, WJ., Geng, Z., Spence, J. et al. Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection. Nature 501, 107–111 (2013). https://doi.org/10.1038/nature12416

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