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

Abstract

Cancer research has been righteously and successfully focused on prevention, early detection and identification of specific molecular targets that distinguish the malignant cells from the neighboring benign cells1. However, a major clinical challenge concerns how we can reduce lethal tissue injury caused by intensive chemoradiotherapy during treatment of late-staged metastatic cancers. Here we tested whether induction of adult stem cells repairs chemoradiation-induced tissue injury and prolongs overall survival. 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 intestinal stem cells (ISCs) and caused villus hypotrophy, whereas Slit2 transgene increased ISCs and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin 1 (Rspo1; a Wnt agonist)5–14 plus Slit2 reduced ISC loss, mitigated gut impairment and protected animals from death, without concomitantly decreasing tumor sensitivity to chemotherapy. Rspo1 and Slit2 may thus act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.

Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

“…Slit2 is expressed by CBCs, along with its receptor roundabout 1 (Robo1). Knockout of Robo1 decreases the number of CBCs, suggesting that a Robo1/Slit2 signaling axis is important for CBC maintenance (Zhou et al, 2013). When administered simultaneously, R-spondin 1 and Slit2 expand the number of Lgr5 + cells, and act synergistically to stimulate intestinal recovery, thereby preventing lethality of mice treated with chemoradiotherapy.…”

“…Together, this ligandreceptor complex associates with and inhibits RNF43 and ZNFR3 (Hao et al, 2012;Koo et al, 2012). The effect of R-spondin 1 on regeneration can be further improved by simultaneous treatment with Slit2 (Zhou et al, 2013). Slit2 is expressed by CBCs, along with its receptor roundabout 1 (Robo1).…”

Molecular cloning and tissue distribution profiles of the chicken R-spondin1 gene

“…In another study, Rspo1 was demonstrated to be a potent and specific mitogen for the gastrointestinal epithelium, and promotes the proliferation of intestinal crypt cells (Kim et al, 2008). A recent study indicates that Slit2 (a nerve migration factor) and Rspo1 cooperatively induce intestinal stem cells for intestinal homeostasis and repair and significantly prolong overall survival following lethal doses of chemoradiotherapy (Zhou et al, 2013).…”

Correction: Radiation enteropathy—pathogenesis, treatment and prevention

“…These interventions seek to increase radiation tolerance, ameliorate secondary normal tissue injury, or enhance repair capacity. Such approaches include, for example, various immunemodulating drugs 74,75 , enterotrophic agents [76][77][78][79][80][81][82][83] , compounds that modulate intraluminal contents 84,85 , and a variety of other strategies [86][87][88][89][90][91] . Interventions that target downstream radiation effects may be generally more appealing in the cancer treatment situation because they do not interfere directly with the mechanism of radiation.…”