Possible mechanisms of the crosstalk between Langerhans cells and regulatory T cells in extramammary Paget disease by receptor activator of nuclear factor kappa B (RANK) ligand/RANK pathways.

Abstract

BACKGROUND:

Extramammary Paget disease (EMPD) is a skin adenocarcinoma of apocrine gland origin, in which Paget cells express receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) and matrix metalloproteinase (MMP)-7, and release soluble (s)RANKL into the tumour microenvironment. We previously reported that about 60% of the RANK+ cells among the stromal cells are M2 macrophages, but the identity of the remaining population of RANK+ cells is still unknown.

OBJECTIVES:

To investigate the unknown subpopulation of RANK-expressing cells in EMPD.

METHODS:

The main population of RANK-expressing cells in the epidermis was composed of epidermal Langerhans cells (LCs). To explore the effects of RANKL on LCs, we stimulated LCs generated from human CD34+ hematopoietic progenitor cells with graded concentrations of sRANKL. To further examine the correlation between LCs and regulatory T cells (Tregs) in EMPD, we employed immunohistochemical staining.

RESULTS:

sRANKL stimulation was shown to augment the production of C-C motif chemokine ligand 17 (CCL17) from LCs. We additionally demonstrated CCL17 expression by CD1a+ LCs in EMPD in an immunofluorescence study. Spearman's rank correlation test confirmed a correlation between the number of LCs and the number of Foxp3+ Tregs in the lesional skin of invasive EMPD. In addition, the numbers of Foxp3+ Tregs in the sentinel lymph nodes of metastatic EMPD were significantly higher than those of metastatic melanoma, which did not express RANKL.

CONCLUSIONS:

The findings suggest that the RANKL/RANK pathway in EMPD might contribute to the recruitment of Tregs and to maintenance of the tumour microenvironment.

• Authors: T Fujimura, Y Kambayashi, S Furudate, A Kakizaki, T Hidaka, S Aiba
• Journal: The British journal of dermatology (Br J Dermatol) Vol. 176 Issue 2 Pg. 387-394 (Feb 2017) ISSN: 1365-2133 [Electronic] England
• PMID: 27411503 (Publication Type: Journal Article)
• Copyright: © 2016 British Association of Dermatologists.

Chemical References

• Chemokine CCL17
• FOXP3 protein, human
• Forkhead Transcription Factors
• NF-kappa B
• RANK Ligand

Topics

• Chemokine CCL17 (metabolism)
• Forkhead Transcription Factors (metabolism)
• Humans
• Langerhans Cells (physiology)
• Lymphatic Metastasis
• NF-kappa B (metabolism)
• Paget Disease, Extramammary (metabolism)
• RANK Ligand (metabolism)
• Receptor Cross-Talk (physiology)
• Skin Neoplasms (metabolism)
• T-Lymphocytes, Regulatory (physiology)
• Tumor Cells, Cultured