Receptor activator of nuclear factor kappa‐B ligand (<scp>RANKL</scp>)/<scp>RANK</scp> signaling promotes cancer‐related inflammation through M2 macrophages

Fujimura, Taku; Kambayashi, Yahiko; Furudate, Sadanori; Kakizaki, Aya; Hidaka, Takanori; Asano, Masayuki; Aiba, Setsuya

doi:10.1111/exd.12949

Cited by 14 publications

(26 citation statements)

References 10 publications

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“…In contrast to the PD‐L1 expression, Paget cells expressed RANKL in 6/6 cases of EMPD, whereas atypical keratinocytes in pagetoid SCCIS did not express RANKL. As we have previously reported, soluble (s)RANKL released from Paget cells stimulates RANK + M2 macrophages to produce chemokines (CCL5 and CCL17) that correlate with the Th2 polarization of naïve T cells and recruitment of Th2 and Tregs . Notably, to our knowledge, there is no English report that describes the metastasis of pagetoid SCCIS.…”

Section: Discussionmentioning

confidence: 79%

RANKL expression is a useful marker for differentiation of pagetoid squamous cell carcinoma in situ from extramammary Paget disease

et al. 2016

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Section: Discussionmentioning

confidence: 79%

RANKL expression is a useful marker for differentiation of pagetoid squamous cell carcinoma in situ from extramammary Paget disease

et al. 2016

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“…Indeed, RANKL‐expressing Paget cells were distributed adjacent to CCL20‐producing cells in the lesion‐affected skin of patients with EMPD (Figure A,B). In addition, IL‐17 promotes development of prostate adenocarcinoma with a concurrent increase in MMP7 expression, and MMP7 cleaves membrane‐associated RANKL to form soluble (s)RANKL, which stimulates TAMs in lesion‐affected skin of adenocarcinoma patients, leading to upregulated expression of several specific chemokines . Based on these observations, we evaluated the serum levels of sCD163 (as a marker of TAM activation) and the chemokines CXCL5, CCL17 and CXCL10.…”

Section: Resultsmentioning

confidence: 99%

Malassezia‐derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra‐mammary Paget's disease

Sato

Fujimura

Tanita

et al. 2019

Experimental Dermatology

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Malassezia yeast play a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)-dependent pathways. Extra-mammary Paget's disease (EMPD) is an adenocarcinoma of apocrine origin, and except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)-17 and related cytokines/ chemokines (IL-23, IL-36γ, CCL20), (b) the expression of these factors in lesion-affected skin in EMPD and (c) the activation of tumor-associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL-36γ mRNA in NHKCs in vitro. In lesion-affected skin of patients with EMPD, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL-23. IL-17-producing cells were distributed adjacent to Paget cells. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR-mediated signalling by epidermal keratinocytes and RANKL-induced recruitment of Th17 cells and TAMs. K E Y W O R D Saryl hydrocarbon receptor, extra-mammary Paget's disease, Malassezia, proinflammatory cytokines, tumor-associated M2 macrophages

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“…They found abundant immunosuppressive cells, such as regulatory T‐cells (Treg) and M2 macrophages within invasive EMPD lesions . They also found Paget cells expressing receptors of activated nuclear factor κB ligand, which stimulate RANK + M2 macrophages . The stimulated M2 macrophages mainly produce chemokines that activate Treg, but also produce other chemokines that maintain an immunosuppressive environment and promote tumor progression.…”

Section: Discussionmentioning

confidence: 99%

“…14 They also found Paget cells expressing receptors of activated nuclear factor κB ligand, which stimulate RANK + M2 macrophages. 15 The stimulated M2 macrophages mainly produce chemokines that activate Treg, but also produce other chemokines that maintain an immunosuppressive environment and promote tumor progression. Whereas more than one carcinogenic stimulus is suspected to be involved in the tumorigenesis of this CSCC, the patient's clinical history was suggestive of immunosuppression playing some role in its development.…”

Section: Discussionmentioning

confidence: 99%

Brain metastasis from cutaneous squamous cell carcinoma coexistent with extramammary Paget's disease: A case report

Kitano

Izumi

Tamura

et al. 2019

Pathology International

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We report a case of cutaneous squamous cell carcinoma (CSCC), initially coexisting with invasive extramammary Paget's disease (EMPD), in the scrotum of an 84‐year‐old man. The patient initially had a rash and pruritus before presenting with a pedunculated scrotal mass surrounded by widespread erythema. He underwent total gastrectomy for adenocarcinoma 1 year previously and had been receiving TS‐1 (Tegafur/Gimeracil/Oteracil pottasium) orally. Histopathologically, the tumor consisted of invasive SCC, with invasive EMPD in the erythematous region. From the clinical presentation and histopathological findings, we assumed that CSCC developed in the background of the EMPD. The CSCC metastasized to several inguinal lymph nodes and to the brain in the following years. While the histogenesis of each of the tumors remains to be elucidated, the fact that the CSCC rather than the EMPD metastasized to a distant site in this patient is to be noted for future treatment considerations.

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Receptor activator of nuclear factor kappa‐B ligand (RANKL)/RANK signaling promotes cancer‐related inflammation through M2 macrophages

Cited by 14 publications

References 10 publications

RANKL expression is a useful marker for differentiation of pagetoid squamous cell carcinoma in situ from extramammary Paget disease

RANKL expression is a useful marker for differentiation of pagetoid squamous cell carcinoma in situ from extramammary Paget disease

Malassezia‐derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra‐mammary Paget's disease

Brain metastasis from cutaneous squamous cell carcinoma coexistent with extramammary Paget's disease: A case report

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