| At present,chemotherapy is one of the major methods of treatment for cancer.Although chemotherapeutic agents(such as cyclophosphamide,paclitaxel,5-fluorouracil)can kill and inhibit the growth of tumor,at the same time,chemo-drugs also can cause some damage to normal tissue and other side effects,the most obvious is hair loss.Only very limited,unsatisfactory therapeutic relief can currently be offered to patients:scalp cooling caps,topical minoxidil therapy and/or a hair prosthesis.Thus,the development of more effective CIA treatment remains a major unmet need in clinical medicine.Feather follicle development and repair offer an excellent,highly tractable model for vertebrate organogenesis,regeneration and epithelial stem cell biology.Here we use the feather follicle to investigate details of this damage response.We show that cyclophosphamide treatment,which causes chemotherapy-induced alopecia in mice and man,induces distinct defects in feather formation.Similar defects are observed in feathers treated with 5-fluorouracil or taxol but not with doxorubicin or arabinofuranosyl cytidine.Selective blockade of cell proliferation was seen in the feather branching area,along with a downregulation of sonic hedgehog(Shh)transcription,but not in the equally proliferative rachis.Then,we show that down-regulation of Shh expression is alsoa critical early event in the damage response of mouse hair follicles to chemotherapy.Disruption of Shh signaling by cyclopamine treatment recapitulated key features of CIA,while supplementation of recombinant Shh protein prevented hair loss.Mechanistically,CAs induce the production of reactive oxygen species and activate Statl signaling.Our results reveal a mechanism through which chemotherapeutic agents damage rapidly proliferating epithelial tissue,namely via the cell population-specific,Shh-dependent inhibition of proliferation.This mechanism may be targeted by future strategies to manage chemotherapy-induced tissue damage. |
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