Dissecting the impact of chemotherapy on the human hair follicle: a pragmatic in vitro assay for studying the pathogenesis and potential management of hair follicle dystrophy.
Chemotherapy-induced alopecia represents one of the major unresolved problems of clinical oncology. The underlying molecular pathogenesis in humans is virtually unknown because of the lack of adequate research models. Therefore, we have explored whether microdissected, organ-cultured, human scalp hair follicles (HFs) in anagen VI can be exploited for dissecting and manipulating the impact of chemotherapy on human HFs. Here, we show that these organ-cultured HFs respond to a key cyclophosphamide metabolite, 4-hydroperoxycyclophosphamide (4-HC), in a manner that resembles chemotherapy-induced HF dystrophy as it occurs in vivo: namely, 4-HC induced melanin clumping and melanin incontinence, down-regulated keratinocyte proliferation, massively up-regulated apoptosis of hair matrix keratinocytes, prematurely induced catagen, and up-regulated p53. In addition, 4-HC induced DNA oxidation and the mitochondrial DNA common deletion. The organ culture system facilitated the identification of new molecular targets for chemotherapy-induced HF damage by microarray technology (eg, interleukin-8, fibroblast growth factor-18, and glypican 6). It was also used to explore candidate chemotherapy protectants, for which we used the cytoprotective cytokine keratinocyte growth factor as exemplary pilot agent. Thus, this novel system serves as a powerful yet pragmatic tool for dissecting and manipulating the impact of chemotherapy on the human HF.
Bodó
Eniko
E
Department of Dermatology, University Hospital Schleswig-Holstein, University of Lübeck, D-23538 Lübeck, Ratzeburger Allee 160, Germany. eniko.bodo@uk-sh.de
Tobin
Desmond J
DJ
Kamenisch
York
Y
Bíró
Tamás
T
Berneburg
Mark
M
Funk
Wolfgang
W
Paus
Ralf
R
D000505:Alopecia / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000235:genetics; D001681:Biological Assay; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free; D003520:Cyclophosphamide / Q000009:adverse effects / Q000031:analogs & derivatives; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D051523:Fibroblast Growth Factor 7 / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D006201:Hair Diseases / Q000139:chemically induced; D018859:Hair Follicle / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009924:Organ Culture Techniques / Q000379:methods*; D010084:Oxidation-Reduction; D017384:Sequence Deletion