DOI: 10.1111/exd.12220 www.wileyonlinelibrary.com/journal/EXD

Commentary from the Editorial Board

Epidermal growth factor receptor and the sebaceous gland Christos C. Zouboulis Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany Correspondence: Christos C. Zouboulis, Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Auenweg 38, 06847 Dessau-Rosslau, Germany, Tel.: ++49-340-5014000, Fax: ++49-340-5014025, e-mail: [email protected] Abstract: Side effects of EGFR inhibition do not include primary sebaceous gland changes. Dahlhoff et al. evaluated EGFR actions on the sebaceous glands in mutant mice with constitutively activated EGFR expression. Enlarged, hyperproliferative sebaceous glands and increased sebum levels were detected, and c-myc levels were increased. These data indicate that EGFR-induced sebocyte mechanisms are probably species-specific. The detected SCD deregulation is compatible with previous reports, whereas SCD is

a marker of sebaceous differentiation, and its expression is essential for lipogenesis. As SCD expression is upregulated by TLR2 activation, there is a link between SCD overexpression and sebaceous differentiation/lipogenesis with inflammation.

Epidermal growth factor (EGF) plays a major role in epithelial homeostasis (1), whereas its receptor (EGFR) has been one of the most targeted receptors in the field of oncology (2) and a major target of endocrine therapy (3). The epithelial side effects of the selective inhibitors of the tyrosine kinase activity of EGFR (4) correlate with the focal epidermal necrosis after EGF inhibition in human skin samples maintained ex vivo (1). Despite these facts and although EGFR has been shown to play important roles during the development, homeostasis and pathology of the hair follicle and the interfollicular epidermis (5), there are few and contradictory data on the role of EGF/EGFR in sebaceous glands, probably due to the rarity of sebaceous tumors. EGF was shown not to affect human sebocyte proliferation in vitro (6) but induced interleukin (IL)-1 secretion (6,7). This finding has been associated with initiation of comedogenesis (8) and follicular hyperkeratosis in vivo and ex vivo (8,9), indicating an increased sebaceous differentiation in vitro. In contrast, EGF inhibited sebaceous differentiation and lipogenesis in human skin maintained ex vivo (9). On the other hand, EGF stimulated proliferation of and suppressed lipogenesis in hamster sebocytes (10). Interestingly, EGFR inhibition treatment affects the hair follicle but does not seem to induce primary changes in the sebaceous gland (7,11,12). In the October issue of this journal, Dahlhoff et al. (13) evaluated EGFR actions on the sebaceous glands by employing Dsk5 mice, a mutant line in which the EGFR is constitutively activated in a ligand-independent manner. Dsk5 mice showed enlarged sebaceous glands and increased sebum secretion levels. The sebaceous glands contained a higher number of cells and showed stronger proliferation. c-myc transcript levels were increased in Dsk5 skin, suggesting that c-myc mediates the proliferative stimuli of the EGFR in the sebaceous gland and confirming previous reports on the positive role of c-myc expression in sebocyte proliferation and sebaceous gland hyperplasia (14). These findings are compatible with the stimulation of hamster sebocyte proliferation under EGF treatment (10) and indicate that EGF-/EGFR-induced mechanisms on sebocytes are probably species-specific. Interestingly, induction of IL-1 expression in human sebocytes in vitro (6)

has been associated with stress culture conditions, whereas hypoxic stress induces the endocytic trafficking of EGFR into cell cytoplasm (15) (Fig. 1). Analysis of differentiation markers by Dahlhoff et al. (13) revealed deregulated expression of stearoyl-CoA desaturase (SCD) 1 and SCD3. SCD1 expression is essential for lipogenesis in mice (16), as sebaceous lipogenesis is affected in Dsk5 mice by EGFR at least via the SCD pathway. Also, in human sebocytes in vitro, SCD upregulation by arachidonic acid as well as linoleic acid treatment led to induction of lipogenesis and enhancement of proinflammatory activity, although SCD downregulation was not followed by reduction of lipogenesis (17). Interestingly, SCD expression is upregulated by the Toll-like receptor (TLR)2 ligand and unspecific bacterial antigen MALP-2 in animal and human models (16,17), a fact that links SCD overexpression and sebaceous differentiation/ lipogenesis with inflammation. Indeed, SCD1 expression is a marker of differentiation in rat preputial sebocytes (18). In conclusion, EGFR may be a regulator of presebocyte proliferation, contributing to the final cell number, to the size and to the lipid output of sebaceous glands, as Dahlhoff et al. (13) declare, however, neither the existing data on the follicular side effects of therapeutic EGFR inhibition provide evidence of sebaceous gland involvement (4) nor the scarce experimental data on human models confirm the results obtained from the studies in mice. Future work on animal and human models may elucidate the possible EGFR-induced mechanisms, which have been

ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 22, 695–696

Key words: cell proliferation – epidermal growth factor receptor – lipid synthesis – sebaceous gland

Accepted for publication 5 August 2013

Figure 1. Possible pathways of EGFR-induced regulation of sebaceous gland (patho) physiology.

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Commentary from the Editorial Board

presented by Dahlhoff et al. (13) and the previous studies. Moreover, the currently detected association of differentially regulated microRNAs during human sebaceous lipogenesis (19) and EGFR involvement in the way of microRNA biogenesis (15) may provide

References

1 Tavakkol A, Varani J, Elder J T et al. Arch Dermatol Res 1999: 291: 643–651. 2 Brand T M, Iida M, Luthar N et al. Radiother Oncol 2013. [Epub ahead of print]. 3 Pritchard K I. J Intern Med 2013: 274: 144–152. 4 Treudler R, Zouboulis C C. Dermatology 2005: 211: 375–376. 5 Schneider M R, Werner S, Paus R et al. Am J Pathol 2008: 173: 14–24. 6 Zouboulis C C, Xia L, Akamatsu H et al. Dermatology 1998: 196: 21–31. 7 Lee W J, Chi S G, Park D J et al. Ann Dermatol 2011: 23: 12–18.

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additional explanations in the still unclarified role of EGF/EGFR in sebaceous gland (patho) physiology.

Conflict of interest The authors have declared no conflicting interests.

8 Ingham E, Eady E A, Goodwin C E et al. J Invest Dermatol 1992: 98: 895–901. 9 Guy R, Ridden C, Kealey T. J Invest Dermatol 1996: 106: 454–460. 10 Akimoto N, Sato T, Sakiguchi T et al. Dermatology 2002: 204: 118–123. 11 Pierard G E, Pierard-Franchimont C, Humbert P. Eur J Dermatol 2012: 22: 54–57. 12 Peuvrel L, Bachmeyer C, Reguiai Z et al. Support Care Cancer 2012: 20: 909–921. 13 Dahlhoff M, Hrabe de Angelis M, Wolf E et al. Exp Dermatol 2013: 22: 667–669. 14 Arnold I, Watt F M. Curr Biol 2001: 11: 558–568.

15 Nishida N, Mimori K, Mori M et al. Cell Res 2013. [Epub ahead of print]. 16 Georgel P, Crozat K, Lauth X et al. Infect Immun 2005: 73: 4512–4521. 17 Zouboulis C C, Angres S, Seltmann H. Br J Dermatol 2011: 165: 269–276. 18 Deplewski D, Qin K, Ciletti N, Rosenfield R L. J Nutr Metab 2011: 2011: 163631. 19 Schneider M R, Samborski A, Bauersachs S et al. J Dermatol Sci 2013: 70: 88–93.

ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 22, 695–696

Epidermal growth factor receptor and the sebaceous gland.

Side effects of EGFR inhibition do not include primary sebaceous gland changes. Dahlhoff et al. evaluated EGFR actions on the sebaceous glands in muta...
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