Original contributionExpression of the glucocorticoid receptor in renal cell neoplasms: an immunohistochemical and quantitative reverse transcriptase polymerase chain reaction study☆
Introduction
Renal cell carcinomas (RCCs) are the most common epithelial neoplasms of the adult kidney. It has been estimated that there will be about 58 240 new cases of kidney cancer in the United States in 2010 and about 13 040 people will die from this disease [1]. The 2004 World Health Organization classification of urinary system tumors subdivides RCCs into several types based on cytoarchitectural features and distinct karyotypic abnormalities [2]. The conventional clear cell type has the highest incidence (70%-80%) and a relatively unfavorable prognosis. Papillary and chromophobe RCCs (CHRCCs) are less common, comprising 10% to 15% and 5% of RCCs, respectively [2], [3] Currently, surgery remains the only effective treatment for RCC, because metastatic disease is highly resistant to radiotherapy and chemotherapy; however, 20% to 30% of patients present with nonresectable metastatic disease, and up to 30% will develop metastatic disease after nephrectomy [4]. Immunotherapy, such as interferon-α and high-dose interleukin (IL)-2, results in only limited response rates of 15% to 20% [5], [6]. Recent advances in targeted molecular therapies with angiogenesis inhibitors, tyrosine kinase inhibitors, and combination treatment modalities have demonstrated improved outcomes; however, the response rates for these novel therapies still remain low [7].
Steroid hormone receptors, including estrogen, progesterone, and androgen receptors, have an essential role in adjuvant therapy of the breast and prostatic cancer; however, they are not expressed or show only low expression levels in RCCs [8], [9], [10]. Recently, using tissue microarray technology, we described the differential expression of the mineralocorticoid receptor, another member of the steroid receptor superfamily, in the distal nephron and its histogenetically related neoplasms: chromophobe carcinoma and oncocytoma (OC) [11]. Because proximal renal tubules have been shown to express glucocorticoid receptors (GRs) [12], we hypothesized that GRs could be differentially expressed in tumors originating from the proximal nephron.
The GR is a member of the steroid receptor superfamily of ligand-regulated transcription factors, which mediates the action of glucocorticoids [13]. After ligand binding, the GR-glucocorticoid complex is translocated to the nucleus, where it mediates either activation or repression of target genes [14]. As a result, glucocorticoids modulate a variety of physiologic and pathologic processes, such as cellular differentiation, growth, inflammation, immune response, carbohydrate metabolism, and regulation of renal fluid and electrolyte homeostasis. Two main human isoforms of GR have been described: GR-α and GR-β [15]. GR-α is the predominant isoform that is expressed in a large number of organs, including brain, liver, kidney, skeletal muscle, lung, and other tissues [16]. In contrast, GR-β expression level is lower than that of the GR-α isoform and is relatively abundant in inflammatory blood cells [16]. Several studies have addressed the expression of GR in neoplastic tissues including adenocarcinomas of the lung, breast, prostate, esophagus, liver, and adrenal [17], [18], [19], [20], [21]; however, its expression in tumors arising in the kidney has not been examined. Our goal was to determine the pattern and prognostic significance of GR expression in renal cell neoplasms (RCNs).
Section snippets
Tissue selection
Tissue samples of RCNs from 200 consecutive patients were collected between the years of 1998 and 2006 from the archives of the Departments of Pathology at the Rhode Island Hospital (RIH) and The Miriam Hospital. None of these patients received adjuvant chemotherapy or radiotherapy before surgery. This study was approved by the institutional review board at the RIH. The cases were stratified into the following groups according to the 2004 World Health Organization classification of urinary
Clinicopathologic characteristics
The clinicopathologic characteristics of the patients with RCNs are summarized in Table 1. Clinical follow-up was available for all cases. The median follow-up period was 36 months (range, 1-88 months).
Immunohistochemical expression of GR in normal renal parenchyma
In the normal kidney cortex, strong nuclear GR expression was present in the glomeruli and in the proximal convoluted tubules, whereas the distal convoluted tubules and collecting ducts were negative (Fig. 1A). In the glomeruli, GR immunoreactivity was seen primarily in epithelial cells
Discussion
In this study, we demonstrated that most CCRCCs strongly express GRs and that there is a significant direct correlation between GR expression and patient survival. GR is a member of the steroid receptor superfamily, which includes a variety of hormone receptors such as the estrogen, progesterone, androgen, and mineralocorticoid receptors. Until recently, the study of steroid receptor expression in RCNs has been largely limited to estrogen and progesterone receptors with discouraging results [8]
References (39)
- et al.
Cytokine-based therapy for metastatic renal cell cancer
Urol Clin North Am
(2003) - et al.
Steroid hormone receptor expression in renal cell carcinoma: an immunohistochemical analysis of 182 tumors
J Urol
(2004) - et al.
The human glucocorticoid receptor: one gene, multiple proteins and diverse responses
Steroids
(2005) - et al.
Glucocorticoid receptor expression in advanced non-small cell lung cancer: clinicopathological correlation and in vitro effect of glucocorticoid on cell growth and chemosensitivity
Lung Cancer
(2006) - et al.
Immunocytochemical analysis of the glucocorticoid receptor alpha isoform (GRalpha) using GRalpha-specific antibody
Steroids
(1999) - et al.
Down-regulation of vascular endothelial growth factor in renal cell carcinoma cells by glucocorticoids
Mol Cell Endocrinol
(2004) - et al.
Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas
FEBS Lett
(1989) - et al.
Inhibitory effect of dexamethasone and progesterone in vitro on proliferation of human renal cell carcinomas and effects on expression of interleukin-6 or interleukin-6 receptor
J Urol
(1995) - et al.
Cancer statistics, 2010
CA Cancer J Clin
(2010)
Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases
Am J Surg Pathol
Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma
J Clin Oncol
Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma
J Clin Oncol
Cytoreductive nephrectomy for metastatic RCC in the era of targeted therapy
Nat Rev Urol
Hormone receptors in renal cancer: an overview
Semin Surg Oncol
Progesterone receptor reactivity in renal oncocytoma and chromophobe renal cell carcinoma
Histopathology
Mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type II expression in renal cell neoplasms: a tissue microarray and quantitative RT-PCR study
Am J Surg Pathol
Glucocorticoid receptors in rat kidney cortical tubules enriched in proximal and distal segments
Am J Physiol
The steroid and thyroid hormone receptor superfamily
Science
Cited by (11)
Current updates and future perspectives on the management of renal cell carcinoma
2021, Life SciencesCitation Excerpt :The level of CD133 mRNA in the blood is helpful for the identification of neoplasms and to project reappearance and is used as an adjunct treatment. Although the expression of the CD133 was investigated in the patients have RCC by IHC was found to be incoherent and diverse among different studies [85–87]. It is also known as CXCL12 and α-chemokine receptor specifically for SDF-1 (stromal-derived factor-1), having a potential chemotactic activity.
First Report of ARID1A Somatic Mutation in a Female Patient with Renal Cell Carcinoma
2016, Clinical Genitourinary CancerCitation Excerpt :The first is the glucocorticoid receptor (GR) that has been identified in physical association with ARID1A.21 GR is strongly expressed in 66% of clear cell RCC, and an abnormal ARID1A could have altered the interaction of glucocorticoids with RCC, leading to an increased proliferation and a presentation with a sizable RCC at such an early age in our patient.22 The other receptor is the estrogen receptor (ER); a recent abstract by Chabot et al23 presented interesting findings when examining the potential role of ARID1A in the regulation of estrogen signaling in ER + breast cancer cells.
Knockdown of NR3C1 inhibits the proliferation and migration of clear cell renal cell carcinoma through activating endoplasmic reticulum stress–mitophagy
2023, Journal of Translational Medicine
- ☆
This study was supported by the Rhode Island Foundation (grant number 20082667) and the Center of Biomedical Research Excellence (COBRE), Center for Cancer Research Development, Molecular Pathology, National Center for Research Resources (grant number P20 RR017695-02).