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 cells. 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) expressed Slit2 and its single-span transmembrane cell-surface receptor roundabout 1 (Robo1). 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) 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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Lineage
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Cell Proliferation / drug effects
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Female
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Homeostasis / drug effects
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / pharmacology
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Intestines / cytology*
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Intestines / drug effects
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Intestines / pathology
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Intestines / radiation effects
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Male
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Mice
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Mice, Inbred C57BL
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Neoplasm Metastasis / drug therapy
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Neoplasm Metastasis / radiotherapy
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Neoplasms / drug therapy*
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Neoplasms / pathology
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Neoplasms / radiotherapy*
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nerve Tissue Proteins / pharmacology
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Receptors, Immunologic / deficiency
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism
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Regeneration / drug effects
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Regeneration / radiation effects
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Roundabout Proteins
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Signal Transduction / drug effects
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Stem Cells / cytology*
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Stem Cells / drug effects
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Stem Cells / metabolism*
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Stem Cells / radiation effects
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Survival Rate
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Thrombospondins / administration & dosage
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Thrombospondins / metabolism*
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Thrombospondins / pharmacology
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Wnt Proteins / metabolism
Substances
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Intercellular Signaling Peptides and Proteins
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Nerve Tissue Proteins
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RSPO1 protein, mouse
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Receptors, Immunologic
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Thrombospondins
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Wnt Proteins
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Slit homolog 2 protein