IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin

Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was fo...

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Bibliographic Details
Published in:Oncotarget 2016-11, Vol.7 (47), p.77138-77151
Main Authors: Dibra, Denada, Mitra, Abhisek, Newman, Melissa, Xia, Xueqing, Keenan, Camille, Cutrera, Jeffry J, Mathis, J Michael, Wang, Xiao-Jing, Myers, Jeffrey, Li, Shulin
Format: Article
Language:English
Subjects:
Animals
CD11b Antigen - genetics
CD11b Antigen - metabolism
Interleukins - metabolism
Mice
Mutation
Proto-Oncogene Proteins p21(ras) - genetics
Pyrrolidines - pharmacology
Receptor, Endothelin A - metabolism
Receptors, Cytokine - genetics
Research Paper
Skin Neoplasms - chemically induced
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Skin Neoplasms - pathology
Stem Cell Niche
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Summary:Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b-/- mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin-a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.12581