Tumor Microenvironment in Functional Adrenocortical Adenomas: Immune Cell Infiltration in Cortisol-producing Adrenocortical Adenoma

Publication date: Available online 27 March 2018
Source:Human Pathology
Author(s): Yuko Kitawaki, Yasuhiro Nakamura, Fumie Kubota-Nakayama, Yuto Yamazaki, Yasuhiro Miki, Shuko Hata, Kazue Ise, Kumi Kikuchi, Ryo Morimoto, Fumitoshi Satoh, Hironobu Sasano
The tumor microenvironment plays pivotal roles in various human neoplasms. However, that of benign tumor, particularly hormone-secreting endocrine tumors, has remained virtually unknown. Therefore, we firstly attempted to analyze the tumor microenvironment of autonomous hormone-secreting adrenocortical adenomas. We first histologically evaluated 21 cortisol-producing adrenocortical adenoma (CPA) and 13 aldosterone-producing adrenocortical adenoma (APA) cases. Quantitative histological analysis revealed that intratumoral immune cell infiltration (ICI) was more pronounced in CPAs than APAs. We then evaluated the cytokines and chemokines profiles using PCR arrays in APAs and CPAs. Angiogenic chemokines, C-X-C Motif Chemokine Ligand (CXCL) 1 and CXCL2, were significantly more abundant in CPAs than APAs using subsequent quantitative PCR and immunohistochemical analyses. We then examined the vascular density between these two adenomas and the density was significantly higher in overt CPAs than in APAs. Of particular interest, CXCL12-positive vessels were detected predominantly in CPAs and their infiltrating immune cells were C-X-C Motif Chemokine Receptor 4 (CXCR4) - positive. These results above indicated that CXCL12-CXCR4 signaling could partly account for ICI detected predominantly in CPAs. We then further explored the etiology of ICI in CPAs by evaluating the senescence of tumor cells possibly caused by excessive cortisol in CPAs. The status of senescence markers, p16 and p21, were significantly more abundant in CPAs than APAs. In addition, all CPA cases examined were positive for senescence-associated β-galactosidase. These results all indicated that exposure to local excessive cortisol could result in senescence of tumors cells and play essential roles in constituting the characteristic tissue microenvironment of CPAs.



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