Treatment of Cultured Sebocytes with an EGFR Inhibitor Does Not Lead to Significant Upregulation of Inflammatory Biomarkers

다국어 초록 (Multilingual Abstract)

Background: Epidermal growth factor receptor (EGFR)inhibitors are being used to treat malignancies originating from epithelia. Unfortunately, blocking the EGFR pathway leads to various side effects, most frequently acneiform eruptions. Objective: To probe the mechanism underlying this side effect, we investigated the effect of EGFR inhibitors on cultured sebocytes. Methods: To examine the effects of an EGFR inhibitor (cetuximab, ErbituxⓇ 10 ng/ml) and the effects of EGFR ligands, such as epidermal growth factor (EGF, 10 ng/ml) and transforming growth factor-α (TGF-α,5 ng/ml), on the production of inflammatory cytokines in cultured sebocytes, we used reverse transcriptase-polymerase chain reaction, immunocytofluorescence and Western blots. Outcomes included the expression of interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α), peroxisome proliferator-activated receptor-γ (PPAR-γ) and EGFR.
Results: There were no significant differences in the expression of IL-1, IL-6, TNF-α, PPAR-γ and EGFR between (a) groups treated with an EGFR inhibitor or an EGFR ligand and (b) the control group, except for a significant increase in the expression of IL-1 in the EGF-treated group. Conclusion:EGFR inhibitors and EGFR ligands do not provoke the expression of inflammatory biomarkers in cultured sebocytes.
The role of the sebaceous glands in EGFR inhibitor-induced acneiform eruption should be investigated more thoroughly. (Ann Dermatol 23(1) 12∼18, 2011)

참고문헌 (Reference)

1 Baselga J, "Why the epidermal growth factor receptor? The rationale for cancer therapy" 7 (7): 2-8, 2002

2 Surguladze D, "Tumor necrosis factor-alpha and interleukin-1 antagonists alleviate inflammatory skin changes associated with epidermal growth factor receptor antibody therapy in mice" 69 : 5643-5647, 2009

3 Pastore S, "The epidermal growth factor receptor system in skin repair and inflammation" 128 : 1365-1374, 2008

4 Pullar CE, "The beta2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms" 119 : 592-602, 2006

5 Li T, "Skin toxicities associated with epidermal growth factor receptor inhibitors" 4 : 107-119, 2009

6 Castillo L, "Pharmacological background of EGFR targeting" 15 : 1007-1012, 2004

7 Siebert PD, "Modified acid guanidinium thiocyanate-phenol-chloroform RNA extraction method which greatly reduces DNA contamination" 21 : 2019-2020, 1993

8 Higashiyama S, "Membrane-anchored growth factors, the epidermal growth factor family: beyond receptor ligands" 99 : 214-220, 2008

9 Lacouture ME, "Mechanisms of cutaneous toxicities to EGFR inhibitors" 6 : 803-812, 2006

10 Ocvirk J, "Management of cutaneous side-effects of cetuximab therapy in patients with metastatic colorectal cancer" 24 : 453-459, 2010

11 Cabodi S, "Integrin regulation of epidermal growth factor (EGF) receptor and of EGF-dependent responses" 32 : 438-442, 2004

12 Lee WJ, "Influence of substance-P on cultured sebocytes" 300 : 311-316, 2008

13 Moore GP, "Hair growth induction: roles of growth factors" 642 : 308-325, 1991

14 Ling YH, "Erlotinib, an effective epidermal growth factor receptor tyrosine kinase inhibitor, induces p27KIP1 up-regulation and nuclear translocation in association with cell growth inhibition and G1/S phase arrest in human non-small-cell lung cancer cell lines" 72 : 248-258, 2007

15 Vallbohmer D, "Epidermal growth factor receptor as a target for chemotherapy" 5 (5): 19-27, 2005

16 Pastore S, "ERK1/2 regulates epidermal chemokine expression and skin inflammation" 174 : 5047-5056, 2005

17 Duvic M, "EGFR inhibitor-associated acneiform folliculitis: assessment and management" 9 : 285-294, 2008

18 Hu JC, "Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management" 56 : 317-326, 2007

19 Gutzmer R, "Cutaneous side effects of EGF-receptor inhibition and their management" 57 : 509-513, 2006

20 Fujie T, "Culture of cells derived from the human sebaceous gland under serum-free conditions without a biological feeder layer or specific matrices" 288 : 703-708, 1996

21 Di Gennaro E, "Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 (‘Iressa’), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells" 195 : 139-150, 2003

22 Segaert S, "Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors" 16 : 1425-1433, 2005

23 Galimont-Collen AF, "Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors" 43 : 845-851, 2007

24 Harding J, "Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody" 41 : 107-127, 2005

25 Molinari E, "Cetuximab-induced acne" 211 : 330-333, 2005

26 Mascia F, "Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation" 163 : 303-312, 2003

27 Yahata Y, "A novel function of angiotensin II in skin wound healing. Induction of fibroblast and keratinocyte migration by angiotensin II via heparin-binding epidermal growth factor (EGF)-like growth factor-mediated EGF receptor transactivation" 281 : 13209-13216, 2006