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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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Proliferation in Egfr controls and mutants was decreased following cyclophosphamide.BrDU (A) and PCNA (B) immunofluorescence was performed in vehicle and cyclophosphamide treated control and mutant mice euthanized at 2 (A-B) or 4 d (A). A) Arrowheads indicate BrDU-labeled matrix keratinocytes, thin arrows BrDU positive epidermal keratinocytes and fat arrows BrDU positive keratinocytes in the distal follicle. BrDU positive cells are red with nuclear DAPI gray. B) PCNA labeled nuclei are green with nuclear DAPI in gray. CYP indicates cyclophosphamide. Scale bar indicates 50 µm.
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pone-0069368-g004: Proliferation in Egfr controls and mutants was decreased following cyclophosphamide.BrDU (A) and PCNA (B) immunofluorescence was performed in vehicle and cyclophosphamide treated control and mutant mice euthanized at 2 (A-B) or 4 d (A). A) Arrowheads indicate BrDU-labeled matrix keratinocytes, thin arrows BrDU positive epidermal keratinocytes and fat arrows BrDU positive keratinocytes in the distal follicle. BrDU positive cells are red with nuclear DAPI gray. B) PCNA labeled nuclei are green with nuclear DAPI in gray. CYP indicates cyclophosphamide. Scale bar indicates 50 µm.

Mentions: To determine whether EGFR deficiency attenuated cyclophosphamide-induced alopecia by altering cell cycle, we examined proliferation following cyclophosphamide treatment. Analysis of BrDU incorporation revealed many vehicle-treated mutant and control matrix cells in S-phase 2 days after treatment (Figure 4A, see arrowheads in panels on left), indicating a typical anagen VI [5]. Following cyclophosphamide, the number of BrDU positive keratinocytes in the hair bulb was strikingly reduced in both controls and mutants (Figure 4A middle panels, arrowheads). However, BrDU positive cells remained in the distal hair follicle and epidermis of both genotypes (Figure 4A middle panels, fat arrow and thin arrows, respectively). Progression to late stages of catagen by 4 days after cyclophosphamide treatment in the control skin was associated with the near cessation of proliferation in the hair follicle (Figure 4A top right, thick arrow). Follicular proliferation resumed at initiation of secondary recovery and new anagen at 8 days (data not shown). Mutant follicles remaining in mid-catagen retained a small number of BrDU positive cells 4 days following cyclophosphamide (Figure 4A bottom right, arrowhead), fewer than at 2 days. The decrease in the proliferation index at 2 days is consistent with catagen entry in cyclophosphamide treated mutants.


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)

Proliferation in Egfr controls and mutants was decreased following cyclophosphamide.BrDU (A) and PCNA (B) immunofluorescence was performed in vehicle and cyclophosphamide treated control and mutant mice euthanized at 2 (A-B) or 4 d (A). A) Arrowheads indicate BrDU-labeled matrix keratinocytes, thin arrows BrDU positive epidermal keratinocytes and fat arrows BrDU positive keratinocytes in the distal follicle. BrDU positive cells are red with nuclear DAPI gray. B) PCNA labeled nuclei are green with nuclear DAPI in gray. CYP indicates cyclophosphamide. Scale bar indicates 50 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3716704&req=5

pone-0069368-g004: Proliferation in Egfr controls and mutants was decreased following cyclophosphamide.BrDU (A) and PCNA (B) immunofluorescence was performed in vehicle and cyclophosphamide treated control and mutant mice euthanized at 2 (A-B) or 4 d (A). A) Arrowheads indicate BrDU-labeled matrix keratinocytes, thin arrows BrDU positive epidermal keratinocytes and fat arrows BrDU positive keratinocytes in the distal follicle. BrDU positive cells are red with nuclear DAPI gray. B) PCNA labeled nuclei are green with nuclear DAPI in gray. CYP indicates cyclophosphamide. Scale bar indicates 50 µm.
Mentions: To determine whether EGFR deficiency attenuated cyclophosphamide-induced alopecia by altering cell cycle, we examined proliferation following cyclophosphamide treatment. Analysis of BrDU incorporation revealed many vehicle-treated mutant and control matrix cells in S-phase 2 days after treatment (Figure 4A, see arrowheads in panels on left), indicating a typical anagen VI [5]. Following cyclophosphamide, the number of BrDU positive keratinocytes in the hair bulb was strikingly reduced in both controls and mutants (Figure 4A middle panels, arrowheads). However, BrDU positive cells remained in the distal hair follicle and epidermis of both genotypes (Figure 4A middle panels, fat arrow and thin arrows, respectively). Progression to late stages of catagen by 4 days after cyclophosphamide treatment in the control skin was associated with the near cessation of proliferation in the hair follicle (Figure 4A top right, thick arrow). Follicular proliferation resumed at initiation of secondary recovery and new anagen at 8 days (data not shown). Mutant follicles remaining in mid-catagen retained a small number of BrDU positive cells 4 days following cyclophosphamide (Figure 4A bottom right, arrowhead), fewer than at 2 days. The decrease in the proliferation index at 2 days is consistent with catagen entry in cyclophosphamide treated mutants.

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