nach oben

Erschienen in:

10.05.2016 | Original Article

Mechanisms of skin aging induced by EGFR inhibitors

verfasst von: Peter Arne Gerber, Bettina Alexandra Buhren, Holger Schrumpf, Peter Hevezi, Edwin Bölke, Dennis Sohn, Reiner U. Jänicke, Viswanath Reddy Belum, Caroline Robert, Mario E. Lacouture, Bernhard Homey

Erschienen in: Supportive Care in Cancer | Ausgabe 10/2016

Einloggen, um Zugang zu erhalten

Abstract

Background

The mechanisms of skin aging have not been completely elucidated. Anecdotal data suggests that EGFR inhibition accelerates aging-like skin changes.

Objective

The objective of the study was to evaluate the clinical characteristics and investigate the cellular and molecular mechanisms underlying skin changes associated with the use of EFGRIs.

Patients and methods

Patients during prolonged treatment with EGFRIs (>3 months) were analyzed for aging-like skin changes. Baseline EGFR expression was compared in young (<25 years old) vs. old (> 65 years old) skin. In addition, the regulation of extracellular matrix, senescence-associated genes, and cell cycle status was measured in primary human keratinocytes treated with erlotinib in vitro.

Results

There were progressive signs of skin aging, including xerosis cutis, atrophy, rhytide formation, and/or actinic purpura in 12 patients. Keratinocytes treated with erlotinib in vitro showed a significant down-modulation of hyaluronan synthases (HAS2 and HAS3), whereas senescence-associated genes (p21, p53, IL-6, maspin) were upregulated, along with a G1 cell cycle arrest and stronger SA β-Gal activity. There was significantly decreased baseline expression in EGFR density in aged skin, when compared to young controls.

Conclusions

EGFR inhibition results in molecular alterations in keratinocytes that may contribute to the observed skin aging of patients treated with respective targeted agents.

Joshi SS, Ortiz S, Witherspoon JN, Rademaker A, West DP, Anderson R, Rosenbaum SE, Lacouture ME (2010) Effects of epidermal growth factor receptor inhibitor-induced dermatologic toxicities on quality of life. Cancer 116:3916–3923CrossRefPubMed

Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812CrossRefPubMed

Gerber PA, Buhren BA, Cevikbas F, Bolke E, Steinhoff M, Homey B (2010) Preliminary evidence for a role of mast cells in epidermal growth factor receptor inhibitor-induced pruritus. J Am Acad Dermatol 63:163–165CrossRefPubMed

Gerber PA, Buhren BA, Homey B (2011) More on aprepitant for erlotinib-induced pruritus. The New England journal of medicine 364:486–487CrossRefPubMed

Gerber PA, Homey B (2008) Images in clinical medicine. Erlotinib-induced hair alterations. The New England journal of medicine 358: 1175

Segaert S, Van Cutsem E (2005) Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO 16:1425–1433CrossRef

Lichtenberger BM, Gerber PA, Holcmann M, Buhren BA, Amberg N, Smolle V, Schrumpf H, Boelke E, Ansari P, Mackenzie C, Wollenberg A, Kislat A, Fischer JW, Rock K, Harder J, Schroder JM, Homey B, Sibilia M (2013) Epidermal EGFR controls cutaneous host defense and prevents inflammation. Science translational medicine 5: 199ra111

Li Y, Liang J, Yang T, Monterrosa Mena J, Huan C, Xie T, Kurkciyan A, Liu N, Jiang D, Noble PW (2016) Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. Matrix biology: journal of the International Society for Matrix Biology. doi:10.1016/j.matbio.2016.03.004

Tzellos TG, Klagas I, Vahtsevanos K, Triaridis S, Printza A, Kyrgidis A, Karakiulakis G, Zouboulis CC, Papakonstantinou E (2009) Extrinsic ageing in the human skin is associated with alterations in the expression of hyaluronic acid and its metabolizing enzymes. Exp Dermatol 18:1028–1035CrossRefPubMed

10.

Rufini A, Tucci P, Celardo I, Melino G (2013) Senescence and aging: the critical roles of p53. Oncogene 32:5129–5143CrossRefPubMed

11.

Childs BG, Durik M, Baker DJ, van Deursen JM (2015) Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 21:1424–1435CrossRefPubMedPubMedCentral

12.

Nickoloff BJ, Lingen MW, Chang BD, Shen M, Swift M, Curry J, Bacon P, Bodner B, Roninson IB (2004) Tumor suppressor maspin is up-regulated during keratinocyte senescence, exerting a paracrine antiangiogenic activity. Cancer Res 64:2956–2961CrossRefPubMed

13.

Garbers C, Kuck F, Aparicio-Siegmund S, Konzak K, Kessenbrock M, Sommerfeld A, Haussinger D, Lang PA, Brenner D, Mak TW, Rose-John S, Essmann F, Schulze-Osthoff K, Piekorz RP, Scheller J (2013) Cellular senescence or EGFR signaling induces interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR). Cell Cycle 12:3421–3432CrossRefPubMedPubMedCentral

14.

Kaya G, Saurat JH (2007) Dermatoporosis: a chronic cutaneous insufficiency/fragility syndrome. Clinicopathological features, mechanisms, prevention and potential treatments. Dermatology 215:284–294CrossRefPubMed

15.

Gerber PA, Enderlein E, Homey B (2008) The Koebner-phenomenon in epidermal growth factor receptor inhibitor-induced cutaneous adverse effects. J Clin Oncol Off J Am Soc Clin Oncol 26:2790–2792CrossRef

16.

Baselga J (2002) Targeting the epidermal growth factor receptor with tyrosine kinase inhibitors: small molecules, big hopes. J Clin Oncol Off J Am Soc Clin Oncol 20:2217–2219CrossRef

17.

Stern RS (2004) Clinical practice. Treatment of photoaging. The New England journal of medicine 350:1526–1534CrossRefPubMed

18.

Iwasa H, Yu S, Xue J, Driscoll M (2010) Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor, PLC-gamma, and IP3R activation. Aging Cell 9:490–505CrossRefPubMed

19.

Rongo C (2011) Epidermal growth factor and aging: a signaling molecule reveals a new eye opening function. Aging 3:896–905CrossRefPubMedPubMedCentral

20.

Yu S, Driscoll M (2011) EGF signaling comes of age: promotion of healthy aging in C. elegans. Exp Gerontol 46:129–134CrossRefPubMed

21.

Shurin GV, Yurkovetsky ZR, Chatta GS, Tourkova IL, Shurin MR, Lokshin AE (2007) Dynamic alteration of soluble serum biomarkers in healthy aging. Cytokine 39:123–129CrossRefPubMed

22.

Green MR, Basketter DA, Couchman JR, Rees DA (1983) Distribution and number of epidermal growth factor receptors in skin is related to epithelial cell growth. Dev Biol 100:506–512CrossRefPubMed

23.

Shiraha H, Gupta K, Drabik K, Wells A (2000) Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness due to preferential loss of EGF receptors. J Biol Chem 275:19343–19351CrossRefPubMed

24.

Jenkins G (2002) Molecular mechanisms of skin ageing. Mech Ageing Dev 123:801–810CrossRefPubMed

25.

Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705CrossRefPubMed

26.

Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118CrossRefPubMedPubMedCentral

27.

Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137CrossRefPubMed

28.

Rodriguez-Fragoso L, Melendez K, Hudson LG, Lauer FT, Burchiel SW (2009) EGF-receptor phosphorylation and downstream signaling are activated by benzo[a]pyrene 3,6-quinone and benzo[a]pyrene 1,6-quinone in human mammary epithelial cells. Toxicol Appl Pharmacol 235:321–328CrossRefPubMedPubMedCentral

29.

Schmidt-Ullrich RK, Mikkelsen RB, Dent P, Todd DG, Valerie K, Kavanagh BD, Contessa JN, Rorrer WK, Chen PB (1997) Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15:1191–1197CrossRefPubMed

30.

Xu Y, Shao Y, Voorhees JJ, Fisher GJ (2006) Oxidative inhibition of receptor-type protein-tyrosine phosphatase kappa by ultraviolet irradiation activates epidermal growth factor receptor in human keratinocytes. J Biol Chem 281:27389–27397CrossRefPubMedPubMedCentral

31.

Kang S, Chung JH, Lee JH, Fisher GJ, Wan YS, Duell EA, Voorhees JJ (2003) Topical N-acetyl cysteine and genistein prevent ultraviolet-light-induced signaling that leads to photoaging in human skin in vivo. The Journal of investigative dermatology 120:835–841CrossRef

32.

Wan YS, Wang ZQ, Shao Y, Voorhees JJ, Fisher GJ (2001) Ultraviolet irradiation activates PI 3-kinase/AKT survival pathway via EGF receptors in human skin in vivo. Int J Oncol 18:461–466PubMed

33.

Xu YR, Fisher GJ (2005) Ultraviolet (UV) light irradiation induced signal transduction in skin photoaging. J Dermatol Sci: S1-S8

34.

Peus D, Vasa RA, Meves A, Beyerle A, Pittelkow MR (2000) UVB-induced epidermal growth factor receptor phosphorylation is critical for downstream signaling and keratinocyte survival. Photochem Photobiol 72:135–140CrossRefPubMed

35.

Ikeyama S, Kusumoto K, Ogata S, Miyake H, Teshima S, Nikawa T, Rokutan K, Tashiro S (1999) A nontoxic heat shock protein 70 inducer, geranylgeranylacetone, prevents apoptosis of primary cultures of rat hepatocyted induced by hydrogen peroxide or ethanol. Gastroenterology 116:A1222–A1222

36.

Davalos AR, Coppe JP, Campisi J, Desprez PY (2010) Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev 29:273–283CrossRefPubMedPubMedCentral

37.

Rock K, Meusch M, Fuchs N, Tigges J, Zipper P, Fritsche E, Krutmann J, Homey B, Reifenberger J, Fischer JW (2012) Estradiol protects dermal hyaluronan/versican matrix during photoaging by release of epidermal growth factor from keratinocytes. J Biol Chem 287:20056–20069CrossRefPubMedPubMedCentral

38.

Haferkamp S, Borst A, Adam C, Becker TM, Motschenbacher S, Windhovel S, Hufnagel AL, Houben R, Meierjohann S (2013) Vemurafenib induces senescence features in melanoma cells. The Journal of investigative dermatology 133:1601–1609CrossRefPubMed

39.

Wang M, Morsbach F, Sander D, Gheorghiu L, Nanda A, Benes C, Kriegs M, Krause M, Dikomey E, Baumann M, Dahm-Daphi J, Settleman J, Willers H (2011) EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks. Cancer Res 71:6261–6269CrossRefPubMedPubMedCentral

40.

Schad K, Baumann Conzett K, Zipser MC, Enderlin V, Kamarashev J, French LE, Dummer R (2010) Mitogen-activated protein/extracellular signal-regulated kinase kinase inhibition results in biphasic alteration of epidermal homeostasis with keratinocytic apoptosis and pigmentation disorders. Clinical cancer research: an official journal of the American Association for Cancer Research 16:1058–1064CrossRef

41.

El-Abaseri TB, Putta S, Hansen LA (2006) Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor. Carcinogenesis 27:225–231CrossRefPubMed

Titel: Mechanisms of skin aging induced by EGFR inhibitors
verfasst von: Peter Arne Gerber
Bettina Alexandra Buhren
Holger Schrumpf
Peter Hevezi
Edwin Bölke
Dennis Sohn
Reiner U. Jänicke
Viswanath Reddy Belum
Caroline Robert
Mario E. Lacouture
Bernhard Homey
Publikationsdatum: 10.05.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Supportive Care in Cancer / Ausgabe 10/2016
Print ISSN: 0941-4355
Elektronische ISSN: 1433-7339
DOI: https://doi.org/10.1007/s00520-016-3254-7

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Springer Medizin

Mechanisms of skin aging induced by EGFR inhibitors

Abstract

Background

Objective

Patients and methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie

Springer Medizin

Abstract

Background

Objective

Patients and methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 10/2016

When fear of cancer recurrence becomes a clinical issue: a qualitative analysis of features associated with clinical fear of cancer recurrence

Sleep disorders in breast cancer survivors

Patient and health care provider perceptions of cancer-related fatigue and pain

Erratum: Erratum to: Effectiveness of tapentadol prolonged release for the management of painful mucositis in head and neck cancers during intensity modulated radiation therapy

Effectiveness of tapentadol prolonged release for the management of painful mucositis in head and neck cancers during intensity modulated radiation therapy

Change in bone mineral density during adjuvant chemotherapy for early-stage breast cancer

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie