Peter Arne Gerber1, Bettina Alexandra Buhren2, Holger Schrumpf2, Peter Hevezi2, Edwin Bölke3, Dennis Sohn4, Reiner U Jänicke4, Viswanath Reddy Belum5, Caroline Robert6, Mario E Lacouture5, Bernhard Homey2. 1. Department of Dermatology, Medical Faculty, University of Düsseldorf, Moorenstrasse 5, D-40225, Duesseldorf, Germany. peterarne.gerber@med.uni-duesseldorf.de. 2. Department of Dermatology, Medical Faculty, University of Düsseldorf, Moorenstrasse 5, D-40225, Duesseldorf, Germany. 3. Clinic and Polyclinic, Radiation Therapy and Radiooncology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany. 4. Laboratory of Molecular Radiooncology, Radiation Therapy and Radiooncology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany. 5. Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 6. Dermatology Service and Paris-Sud University, Gustave Roussy Cancer Campus, Villejuif-Paris Sud, Paris, France.
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.
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.
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