Elsevier

Human Pathology

Volume 84, February 2019, Pages 124-132
Human Pathology

Original contribution
The expression of sex steroid receptors and sex steroid–synthesizing/metabolizing enzymes in metastasized lymph nodes of prostate cancer

https://doi.org/10.1016/j.humpath.2018.09.011Get rights and content

Highlights

  • Sex steroid–related enzymes were expressed in metastasized lymph nodes of prostate cancer.

  • Local sex steroid metabolism plays pivotal roles in metastasized lymph nodes of prostate cancer.

  • The effects of sex steroids maybe different between metastasized lymph nodes and primary lesion.

Summary

The expression statuses of sex steroid receptors and sex steroid–synthesizing/metabolizing enzymes have been reported in primary prostate cancer lesions, but that in metastatic lymph nodes has remained unknown. Therefore, in this study, we immunolocalized these proteins in primary tumors and paired metastatic lymph nodes of prostate cancer and correlated the findings with clinicopathological factors of individual patients. The expression statuses of AR and ER β was significantly increased in metastatic lymph nodes compared with primary lesions, whereas that of 17βHSD1, 17βHSD2, 17βHSD5, and STS immunoreactivity was decreased in metastatic lymph nodes. In metastatic lymph nodes, the status of 5α2 was significantly correlated with that of AR. In addition, 17βHSD5-, 5α1-, STS-, and EST-positive cases were significantly associated with Gleason score (GS) status (GS > 8 versus GS < 7) in metastatic lymph nodes. Results of our present study did demonstrate that in situ androgen and estrogen metabolism and action play roles in pathophysiology of prostate cancer in metastatic lymph nodes, but these steroidogenic effects could be different from those in primary lesions.

Introduction

Prostate cancer is known as the most common cancer in men, with blockade of androgen production and/or actions via various means (ADT) being one of the standard treatments [1]. However, the ability of the prostate tissue to produce its own androgen from circulating precursors suggests one means by which cancers may escape therapeutic effects. We previously reported that several androgen-producing enzymes 5α1, 5α2, and 17βHSD5 were expressed in prostate cancer cases, and the statuses of these enzymes were associated with more adverse clinical factors [2]. Based on these findings, it is postulated that in situ production of DHT from inactive androstenedione by 17βHSD5 (reduction of androstenedione to testosterone), and via 5α1 or 5α2 (metabolism of testosterone to DHT) in human prostate cancer could occur and drive prostate cancer growth [2] through its actions at the AR [3].

The importance of local estrogen production and metabolism in regulating the behavior of prostate carcinoma cells has also been previously reported. The androgen and estrogen pathway are both implicitly linked because androgens serve as the obligate precursor for the synthesis of estrogens. Therefore, an availability of localized estrogens is regulated by a number of enzymes summarized in Fig. 1. Aromatase converts circulating or localized androgens (androstenedione and testosterone) into estrogens (E1 and E2) and 17βHSD1 (the reduction of E1 to E2), whereas 17βHSD2 converts from E2 to E1, STS hydrolyzes E1S to E1, and EST sulfonates E1 to E1S [4], [5], [6]. We previously reported immunolocalization of EST and STS, as well as ERβ in prostate cancer tissues obtained from surgery [7]. Aromatase expression in carcinoma cells and cancer stromal cells in prostate cancer cases have been reported to be associated with increased time to biochemical failure and clinical failure [8], suggesting the importance of this pathway in developing therapeutic resistance.

Despite their characterization in primary lesion of prostate cancer, the statuses of these receptors and enzymes and their possible correlation with clinicopathological findings have not been examined in metastatic lymph nodes of prostate cancer cases. The status of those above in metastatic lymph nodes of prostate cancer cases could be important because the cases with therapeutic resistance often correspond to metastatic cases in which little is known about their potential for intracrine metabolism of steroids and thus sensitivity to drugs targeting this pathway. Therefore, in this study, we first immunolocalized AR, ERβ, 5α isozymes, 17βHSD isoforms, STS, EST, and aromatase in metastatic lymph nodes of prostate cancer tissue specimens. We then evaluated the possible roles of these AR/ERβ and sex steroid–synthesizing/metabolizing enzymes in metastatic lymph nodes of prostate cancer. In addition, we examined the status of these receptors and enzymes in distant metastatic lesions.

Section snippets

Materials and methods

Sixty-three pairs of specimens from both primary lesion and metastatic sites to lymph nodes in prostate cancer cases were obtained from patients who underwent surgical resections in Tohoku University Hospital (Sendai, Japan), The Jikei University Hospital (Tokyo, Japan), Sendai Medical Center (Sendai, Japan), and JCHO Sendai Hospital (Sendai, Japan), respectively. Three cases of lung metastases (resection) and 4 bone metastases (biopsy) were also obtained from The Jikei University Hospital and

Immunohistochemical evaluation between primary lesion versus lymph node metastases

AR and ERβ immunoreactivity was both detected in the nuclei of cancer cells, whereas immunoreactivity of 17βHSD5, 5α1, 5α2, STS, EST, aromatase, 17βHSD1, and 17βHSD2 was detected in the cytoplasm of carcinoma cells in both primary lesion and metastatic lymph node (Fig. 2, Fig. 3). The statuses of AR and ERβ expression were significantly higher in metastatic lymph node compared with primary lesion (Table 1). On the other hand, the relative expression statuses of 17βHSD1, 17βHSD2, 17βHSD5, and

Discussion

Sex steroid hormones, including androgens and estrogens, are known to play important roles in various target tissue including normal human prostate, prostate cancer, and benign prostatic hyperplasia [2], [7], [10], [11]. Therefore, in this study, we reported the presence of the AR and ERβ in primary prostate cancer, metastatic lymph nodes, and distant metastatic lesion with relevant enzymes (17βHSD1, 17βHSD2, 17βHSD5, 5α1, 5α2, STS, EST, and aromatase), indicating that in situ androgen and

Supplementary data

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Supplementary tables

References (18)

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    AKR1C3 was found to be significantly up-regulated in metastasis tissues in this study, which was similar with their previous research [66,71], leading to the increase of androgen levels. However, Nakamura et al. also reported that AKR1C3 was upregulated in metastasis tissues by immunohistochemical data [72]. This is a point in which not all information in the literature confirm the same results, which can happen and may need further attention.

  • Steroid sulfatase inhibitors: the current landscape

    2021, Expert Opinion on Therapeutic Patents

Disclosures: The authors declare no conflicts of interest. The authors have no funding to report.

1

These authors contributed equally to this work.

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