Abstract
Patients who undergo pelvic radiotherapy may develop severe and chronic complications resulting from gastrointestinal alterations. The lack of curative treatment highlights the importance of novel and effective therapeutic strategies. We thus tested the therapeutic benefit of mesenchymal stem cells (MSC) treatment and proposed molecular mechanisms of action. MSC efficacy was tested in an experimental model of radiation-induced severe colonic ulceration histologically similar to that observed in patients. In this model, MSC from bone marrow were administered intravenously, immediately or three weeks (established lesions) after irradiation. MSC therapy reduces radiation-induced colonic ulceration and increases animal survival. MSC treatment induces therapeutic efficacy whatever the time of cell infusion. Infused-MSC engraft in the colon but also increase endogenous MSC mobilization in blood that have lasting benefits over time. In vitro analysis demonstrates that the MSC effect is mediated by paracrine mechanisms through the non-canonical WNT (Wingless integration site) pathway. In irradiated rat colons, MSC treatment increases the expression of the non-canonical WNT4 ligand by epithelial cells. The epithelial regenerative process is improved after MSC injection by stimulation of colonic epithelial cells positive for SOX9 (SRY-box containing gene 9) progenitor/stem cell markers. This study demonstrates that MSC treatment induces stimulation of endogenous host progenitor cells to improve the regenerative process and constitutes an initial approach to arguing in favor of the use of MSC to limit/reduce colorectal damage induced by radiation.
Highlights
Pelvic radiotherapy is an established part of treatment of both primary and recurrent pelvic malignancies, including colorectal, urologic, and gynecologic cancers
We detected 695.6657.9 pg/ml in the irradiated group and 1161.2691.1 pg/ml in irradiated and mesenchymal stem cells (MSC) treated group, i.e. a 1.7-fold (p,0.05) increase induced after MSC treatment. These results suggest that mobilization of endogenous MSC into the bloodstream induced by MSC-based therapy could be at least stimulated by the secretion of paracrine factor such as SDF-1a
We reported functional parameter modifications in this zone, which are not observed after MSC treatment
Summary
Pelvic radiotherapy is an established part of treatment of both primary and recurrent pelvic malignancies, including colorectal, urologic, and gynecologic cancers. The efficacy of radiotherapy requires an optimal compromise between tumor control and toxicity to healthy, non-neoplastic tissues. As a result of pelvic radiotherapy, non-neoplastic tissue present in the irradiation field near the tumor can be damaged, leading to acute and/or chronic symptoms, the condition labeled as ‘‘pelvic-radiation disease’’ by Andreyev et al [1]. Advances in the quality of radiation treatment have improved tumor control, increasing the number of cancer survivors suffering from treatment-related adverse effects. Gastrointestinal symptoms induced by chronic toxicity of irradiation have the greatest effect on patient quality of life. It is estimated that 90% of patients subjected to pelvic radiotherapy develop acute side effects (nausea, alternation of diarrhea and constipation, vomiting and abdominal pain) with permanent changes to their bowel habits. After 20 years, 20% of patients develop severe late side effects (diarrhea, rectal bleeding, tenesmus and occlusion) associated with high morbidity and mortality [2]
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