Abstract
Abundant mast cell infiltration and disease initiation at puberty are hallmark features of cutaneous neurofibroma (cNF). However, the association between mast cell infiltration and steroid hormones in cNF remains unclear. Here, we determined that androgen receptor (AR) expression is positively associated with mast cell density in cNF tissues. Moreover, both in vitro cell experiments and in vivo mouse models verified that activated AR promoted mast cell infiltration and that AR inhibition reduced mast cell infiltration. Analyses in cell models and xenograft tumours both demonstrated that AR upregulated Yes associate protein 1 (YAP)-adrenomedullin (AM) signalling. Clinical samples from cNF patients further verified that AR was positively related to YAP and AM. Mechanistic analysis revealed that AR accelerates AM transcription via enhancing YAP- TEA domain transcription factor (TEAD) binding to the AM promoter. Consequently, the upregulated AM enhanced mast cell recruitment. Interruption of the YAP-TEAD interaction or inhibition of AM could impair mast cell accumulation induced by active AR, which indicated that this newly found signalling pathway may provide novel targets for cNF treatment.
Highlights
Abundant mast cell infiltration and disease initiation at puberty are hallmark features of cutaneous neurofibroma
To investigate the potential association of androgen receptor (AR) expression and mast cell infiltration, the major immune cells in the cutaneous neurofibroma (cNF) tumour microenvironment (TME) were subjected to immunohistochemistry (IHC) analyses with anti-tryptase[16] and anti-AR antibodies in 40 cNF tissues and adjacent normal tissues
The results revealed that mast cell density (MCD) was significantly increased in cNF tissues compared to adjacent normal tissues (3.875 ± 0.369 per high power field (HPF) vs 0.425 ± 0.1597 per HPF, P < 0.001, Fig. 1a,b)
Summary
Abundant mast cell infiltration and disease initiation at puberty are hallmark features of cutaneous neurofibroma (cNF). Interruption of the YAP-TEAD interaction or inhibition of AM could impair mast cell accumulation induced by active AR, which indicated that this newly found signalling pathway may provide novel targets for cNF treatment. Some patients showed increased progression of cNF and upregulated malignant potential of pNF during pregnancy[4,5] These data suggest that steroid hormones may play a role in neurofibroma initiation, development and maintenance. We found that active AR facilitated mast cell infiltration via accelerating the interaction of the YAP-TEAD complex with the adrenomedullin (AM) promoter As both steroid hormones and YAP play important roles in mediating mast cell activity, the therapeutic potency of targeting the newly investigated pathway to suppress mast cell infiltration is worth further exploration
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