Kambayashi Yumi, Fujimura Taku, Furudate Sadanori, Lyu Chunbing, Hidaka Takanori, Kakizaki Aya, Sato Yota, Tanita Kayo, Aiba Setsuya
Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan
Anticancer Res. 2018 Jan;38(1):113-120. doi: 10.21873/anticanres.12198.
Primary cutaneous apocrine carcinoma (PCAC) is a rare and highly aggressive tumor entity. Since there is no conventional therapy for advanced PCAC, exploratory treatments are sometimes used. As we previously reported, receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL)/RANK signaling on M2 macrophages promotes the production of chemokines and proinflammatory cytokines to maintain the immunosuppressive tumor environment of extramammary Paget's disease (EMPD). Since EMPD is a skin adenocarcinoma of apocrine gland origin that expresses high levels of RANKL and matrix metalloproteinase (MMP) 7, and EMPD is associated with the presence of RANK M2 macrophages, we hypothesized that tumor-associated macrophages (TAMs) in adenocarcinomas such as PCAC might also express RANKL and MMP7.
We employed immunohistochemical staining of RANKL and MMP7 in the lesional skin from five patients with PCAC, and microarray analysis of MMPs using human monocyte-derived macrophages.
According to DNA microarray analysis, the expression of MMP1 and MMP25 was augmented. The DNA microarray results were verified by using real-time polymerase chain reaction (RT-PCR). Immunohistochemical staining of MMP1 and MMP25 as well as chemokine (C-C motif) ligand (CCL) 5 in the lesional skin from five patients with PCAC showed a substantial number of MMP1-bearing cells and MMP25-bearing cells, as well as CCL5-producing cells, that were distributed in the lesional skin.
Our study suggests that the RANKL/RANK pathway contributes to the development and maintenance of the immunosuppressive tumor microenvironment and denosumab may be a promising adjuvant therapy targeting TAMs in cancer of apocrine origin.
原发性皮肤大汗腺癌（PCAC）是一种罕见且侵袭性很强的肿瘤实体。由于晚期PCAC没有常规治疗方法，有时会采用探索性治疗。正如我们之前报道的，M2巨噬细胞上的核因子κB受体激活剂（RANK）配体（RANKL）/RANK信号通路促进趋化因子和促炎细胞因子的产生，以维持乳腺外佩吉特病（EMPD）的免疫抑制肿瘤环境。由于EMPD是一种起源于大汗腺的皮肤腺癌，表达高水平的RANKL和基质金属蛋白酶（MMP）7，且EMPD与RANK M2巨噬细胞的存在有关，我们推测PCAC等腺癌中的肿瘤相关巨噬细胞（TAM）也可能表达RANKL和MMP7。
我们对5例PCAC患者病变皮肤中的RANKL和MMP7进行了免疫组织化学染色，并用人单核细胞衍生的巨噬细胞对MMP进行了微阵列分析。
根据DNA微阵列分析，MMP1和MMP25的表达增加。DNA微阵列结果通过实时聚合酶链反应（RT-PCR）得到验证。对5例PCAC患者病变皮肤中的MMP1、MMP25以及趋化因子（C-C基序）配体（CCL）5进行免疫组织化学染色，结果显示病变皮肤中有大量含MMP1的细胞、含MMP25的细胞以及产生CCL5的细胞分布。
我们的研究表明，RANKL/RANK通路有助于免疫抑制肿瘤微环境的发展和维持，地诺单抗可能是一种有前景的针对大汗腺起源癌症中TAM的辅助治疗药物。
