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

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 cells(1). 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.