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Role for the epidermal growth factor receptor in chemotherapy-induced alopecia.

Bichsel KJ, Gogia N, Malouff T, Pena Z, Forney E, Hammiller B, Watson P, Hansen LA - PLoS ONE (2013)

Bottom Line: Because the epidermal growth factor receptor (EGFR) signals anagen hair follicles to enter catagen, we hypothesized that EGFR signaling may be involved in cyclophosphamide-induced alopecia.Egfr mutant skin entered catagen normally, as indicated by dermal papilla condensation and decreased follicular proliferation, but did not progress to telogen as did Egfr wild type follicles.Egfr mutant follicles responded with less proliferation, apoptosis, and fewer p53-positive cells after cyclophosphamide.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska, United States of America.

ABSTRACT
Treatment of cancer patients with chemotherapeutics like cyclophosphamide often causes alopecia as a result of premature and aberrant catagen. Because the epidermal growth factor receptor (EGFR) signals anagen hair follicles to enter catagen, we hypothesized that EGFR signaling may be involved in cyclophosphamide-induced alopecia. To test this hypothesis, skin-targeted Egfr mutant mice were generated by crossing floxed Egfr and Keratin 14 promoter-driven Cre recombinase mice. Cyclophosphamide treatment of control mice resulted in alopecia while Egfr mutant skin was resistant to cyclophosphamide-induced alopecia. Egfr mutant skin entered catagen normally, as indicated by dermal papilla condensation and decreased follicular proliferation, but did not progress to telogen as did Egfr wild type follicles. Egfr mutant follicles responded with less proliferation, apoptosis, and fewer p53-positive cells after cyclophosphamide. Treatment of control mice with the EGFR inhibitors erlotinib or gefitinib similarly suppressed alopecia and catagen progression by cyclophosphamide. Secondary analysis of clinical trials utilizing EGFR-targeted therapies and alopecia-inducing chemotherapy also revealed evidence for involvement of EGFR in chemotherapy-induced alopecia. Taken together, our results demonstrated the involvement of EGFR signaling in chemotherapy-induced alopecia, which will help in the design of novel therapeutic regimens to minimize chemotherapy-induced alopecia.

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Inhibition of EGFR reduces cyclophosphamide-induced alopecia.Beginning at P12, groups of FVB/N mice were topically treated each day on the dorsal skin with gefitinib, erlotinib, or with the vehicle alone (the dorsal hair was lightly trimmed with electric clippers prior to the first treatment). Two hours after the first treatment, the mice were injected with cyclophosphamide. The mice were monitored daily for alopecia, and euthanized 3 (A,D-F) or 9 d (B-C) later. The mice were photographed (B), skin removed for immunoblotting with the indicated antibodies (A), dorsal skin sections stained with hematoxylin and eosin (C), or immunofluorescence for BrDU (D), PCNA (E), or p53 (F) performed. Arrowheads (D-E) indicate proliferating cells. Images are representative of the two-three mice per group. Scale bar indicates 100 µm.
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pone-0069368-g006: Inhibition of EGFR reduces cyclophosphamide-induced alopecia.Beginning at P12, groups of FVB/N mice were topically treated each day on the dorsal skin with gefitinib, erlotinib, or with the vehicle alone (the dorsal hair was lightly trimmed with electric clippers prior to the first treatment). Two hours after the first treatment, the mice were injected with cyclophosphamide. The mice were monitored daily for alopecia, and euthanized 3 (A,D-F) or 9 d (B-C) later. The mice were photographed (B), skin removed for immunoblotting with the indicated antibodies (A), dorsal skin sections stained with hematoxylin and eosin (C), or immunofluorescence for BrDU (D), PCNA (E), or p53 (F) performed. Arrowheads (D-E) indicate proliferating cells. Images are representative of the two-three mice per group. Scale bar indicates 100 µm.

Mentions: In order to determine whether EGFR inhibitors could block cyclophosphamide-induced alopecia, groups of wild type mice were topically treated with EGFR inhibitors erlotinib, gefitinib or vehicle alone prior to cyclophosphamide treatment, and alopecia monitored. Mice were treated daily with the inhibitors throughout the course of the experiment, resulting in decreased phospho-EGFR on immunoblot, used as a measure of EGFR activity, when compared to the vehicle treated mice (Figure 6A). After 3d of either erlotinib or gefitinib treatment, phospho-EGFR was reduced by approximately 60% when compared to the vehicle treated control (Figure 6A).While cyclophosphamide-treated mice began to lose hair by 6 d after treatment regardless of EGFR inhibitor status (not shown), alopecia was more pronounced in the vehicle-treated compared to the inhibitor-treated mice. By 9 d after cyclophosphamide injection, hair loss was substantial in the vehicle treated and cyclophosphamide injected mice (Figure 6B left). In contrast, EGFR inhibitor treated and cyclophosphamide injected mice sustained substantially less alopecia (Figure 6B, middle and right-hand panels). Histological examination revealed a progression to late catagen in vehicle-treated follicles (Figure 6C left) while EGFR inhibitor treated follicles remained elongated into the subcutis (Figure 6C, middle and right-hand panels), and shared characteristics with Egfr mutant follicles (Figure 2). EGFR inhibitor treated hair follicles failed to progress beyond mid-dystrophic catagen following cyclophosphamide (Figure 6C, middle and right-hand panels). As in the Egfr mutant mice after cyclophosphamide, vehicle and inhibitor treated mice had similar levels of proliferation as indicated by BrDU (Figure 6D, arrowheads) and PCNA (Figure 6E, arrowheads) immunofluorescence but inhibitor treated mice had fewer p53-positive cells at 3d post-cyclophosphamide (Figure 6F). Thus, EGFR inhibitors administered prior to cyclophosphamide provided partial protection from cyclophosphamide-induced alopecia in mice.


Role for the epidermal growth factor receptor in chemotherapy-induced alopecia.

Bichsel KJ, Gogia N, Malouff T, Pena Z, Forney E, Hammiller B, Watson P, Hansen LA - PLoS ONE (2013)

Inhibition of EGFR reduces cyclophosphamide-induced alopecia.Beginning at P12, groups of FVB/N mice were topically treated each day on the dorsal skin with gefitinib, erlotinib, or with the vehicle alone (the dorsal hair was lightly trimmed with electric clippers prior to the first treatment). Two hours after the first treatment, the mice were injected with cyclophosphamide. The mice were monitored daily for alopecia, and euthanized 3 (A,D-F) or 9 d (B-C) later. The mice were photographed (B), skin removed for immunoblotting with the indicated antibodies (A), dorsal skin sections stained with hematoxylin and eosin (C), or immunofluorescence for BrDU (D), PCNA (E), or p53 (F) performed. Arrowheads (D-E) indicate proliferating cells. Images are representative of the two-three mice per group. Scale bar indicates 100 µm.
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Related In: Results  -  Collection

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pone-0069368-g006: Inhibition of EGFR reduces cyclophosphamide-induced alopecia.Beginning at P12, groups of FVB/N mice were topically treated each day on the dorsal skin with gefitinib, erlotinib, or with the vehicle alone (the dorsal hair was lightly trimmed with electric clippers prior to the first treatment). Two hours after the first treatment, the mice were injected with cyclophosphamide. The mice were monitored daily for alopecia, and euthanized 3 (A,D-F) or 9 d (B-C) later. The mice were photographed (B), skin removed for immunoblotting with the indicated antibodies (A), dorsal skin sections stained with hematoxylin and eosin (C), or immunofluorescence for BrDU (D), PCNA (E), or p53 (F) performed. Arrowheads (D-E) indicate proliferating cells. Images are representative of the two-three mice per group. Scale bar indicates 100 µm.
Mentions: In order to determine whether EGFR inhibitors could block cyclophosphamide-induced alopecia, groups of wild type mice were topically treated with EGFR inhibitors erlotinib, gefitinib or vehicle alone prior to cyclophosphamide treatment, and alopecia monitored. Mice were treated daily with the inhibitors throughout the course of the experiment, resulting in decreased phospho-EGFR on immunoblot, used as a measure of EGFR activity, when compared to the vehicle treated mice (Figure 6A). After 3d of either erlotinib or gefitinib treatment, phospho-EGFR was reduced by approximately 60% when compared to the vehicle treated control (Figure 6A).While cyclophosphamide-treated mice began to lose hair by 6 d after treatment regardless of EGFR inhibitor status (not shown), alopecia was more pronounced in the vehicle-treated compared to the inhibitor-treated mice. By 9 d after cyclophosphamide injection, hair loss was substantial in the vehicle treated and cyclophosphamide injected mice (Figure 6B left). In contrast, EGFR inhibitor treated and cyclophosphamide injected mice sustained substantially less alopecia (Figure 6B, middle and right-hand panels). Histological examination revealed a progression to late catagen in vehicle-treated follicles (Figure 6C left) while EGFR inhibitor treated follicles remained elongated into the subcutis (Figure 6C, middle and right-hand panels), and shared characteristics with Egfr mutant follicles (Figure 2). EGFR inhibitor treated hair follicles failed to progress beyond mid-dystrophic catagen following cyclophosphamide (Figure 6C, middle and right-hand panels). As in the Egfr mutant mice after cyclophosphamide, vehicle and inhibitor treated mice had similar levels of proliferation as indicated by BrDU (Figure 6D, arrowheads) and PCNA (Figure 6E, arrowheads) immunofluorescence but inhibitor treated mice had fewer p53-positive cells at 3d post-cyclophosphamide (Figure 6F). Thus, EGFR inhibitors administered prior to cyclophosphamide provided partial protection from cyclophosphamide-induced alopecia in mice.

Bottom Line: Because the epidermal growth factor receptor (EGFR) signals anagen hair follicles to enter catagen, we hypothesized that EGFR signaling may be involved in cyclophosphamide-induced alopecia.Egfr mutant skin entered catagen normally, as indicated by dermal papilla condensation and decreased follicular proliferation, but did not progress to telogen as did Egfr wild type follicles.Egfr mutant follicles responded with less proliferation, apoptosis, and fewer p53-positive cells after cyclophosphamide.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska, United States of America.

ABSTRACT
Treatment of cancer patients with chemotherapeutics like cyclophosphamide often causes alopecia as a result of premature and aberrant catagen. Because the epidermal growth factor receptor (EGFR) signals anagen hair follicles to enter catagen, we hypothesized that EGFR signaling may be involved in cyclophosphamide-induced alopecia. To test this hypothesis, skin-targeted Egfr mutant mice were generated by crossing floxed Egfr and Keratin 14 promoter-driven Cre recombinase mice. Cyclophosphamide treatment of control mice resulted in alopecia while Egfr mutant skin was resistant to cyclophosphamide-induced alopecia. Egfr mutant skin entered catagen normally, as indicated by dermal papilla condensation and decreased follicular proliferation, but did not progress to telogen as did Egfr wild type follicles. Egfr mutant follicles responded with less proliferation, apoptosis, and fewer p53-positive cells after cyclophosphamide. Treatment of control mice with the EGFR inhibitors erlotinib or gefitinib similarly suppressed alopecia and catagen progression by cyclophosphamide. Secondary analysis of clinical trials utilizing EGFR-targeted therapies and alopecia-inducing chemotherapy also revealed evidence for involvement of EGFR in chemotherapy-induced alopecia. Taken together, our results demonstrated the involvement of EGFR signaling in chemotherapy-induced alopecia, which will help in the design of novel therapeutic regimens to minimize chemotherapy-induced alopecia.

Show MeSH
Related in: MedlinePlus