Olfactory receptor 51E1 as a novel target for diagnosis in somatostatin receptor-negative lung carcinoids

Giandomenico, Valeria; Tao, Cui; Grimelius, Lars; Öberg, Kjell; Pelosi, Giuseppe; Tsolakis, Apostolos V.

doi:10.1530/jme-13-0144

Cited by 42 publications

(43 citation statements)

References 26 publications

(30 reference statements)

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“…DR2 is expressed more frequently in ACs than TCs [11]. OR51E1 expression is detected in the majority of SSTR-negative LCs [12], and IGF-1, IGF-1R, CTGF and HIF-1 are expressed in the majority of LCs [13]. In this study, SSR status and that of the aforementioned novel IHC markers was shown to lack any prognostic value for OS and EFS in LCs.…”

Section: Discussionmentioning

confidence: 77%

“…Additionally, the localization of receptor expression was assessed semi-quantitatively based on the classification by Volante et al [19] as follows: Score 1 (S1): pure cytoplasmic immunoreactivity; score 2 (S2): a minority tumour cell population showed membranous immunoreactivity in < 50% of the cell circumference, and score 3 (S3): a majority tumour cell population revealed membranous immunoreactivity in over 50% of the circumference [11, 12, 19]. The intensity of IHC staining for the IGF-1, IGF -1R, CTGF and HIF-1 antibodies were rendered only quantitatively with a 50% cut-off [20].…”

Section: Methodsmentioning

confidence: 99%

“…The high and variable Immunohistochemical (IHC) expression of the majority of somatostatin receptors (SSTRs) along with their co-expression with dopamine receptor 2 (DR2), as well as the expression of olfactory receptor 51E1 (OR51E1) in SS-negative LCs, have been previously addressed, providing a rationale for potentially novel diagnostic markers that may be utilized as therapeutic targets [11, 12]. Additionally, the expression of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), connective tissue growth factor (CTGF) and hypoxia factor-1 (HIF-1) has recently been confirmed in these patients [13].…”

Section: Introductionmentioning

confidence: 99%

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Lung Carcinoids: Long-Term Surgical Results and the Lack of Prognostic Value of Somatostatin Receptors and Other Novel Immunohistochemical Markers

Daskalakis¹,

Kaltsas²,

Öberg³

et al. 2018

Neuroendocrinology

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Background/Aims: Lung carcinoids (LCs) are often diagnosed at an early stage and surgical intervention becomes the next phase of treatment. To date, there is lack of long-term follow-up data after surgery and prognostication based on WHO classification criteria and evolving prognostic markers, particularly the expression of somatostatin receptors (SSR). Methods: We included 102 consecutive patients (72 women; age at baseline 51 ± 16 years [mean ± SD]) with LCs, who underwent thoracic surgery (n = 99) and/or laser treatment (n = 8). Hospital charts were reviewed for clinico-pathological parameters. Immunohistochemical (IHC) expression of SSR1–5 and other novel markers were studied with regard to their prognostic value. Results: Five- and 10-year overall survival (OS) was 96 and 83% respectively; relative survival (RS) was 101 and 93% respectively; and event-free survival (EFS) was 80 and 67% respectively. Independent prognostic factors for OS, RS and/or EFS were age at diagnosis, histopathological type and the presence of ipsilateral mediastinal subcarinal lymph node metastases. Macro-radicality of resective surgery and its extent were associated with increased OS and EFS. The IHC expression of SSR1–5 and other novel markers was not associated with OS or EFS. Conclusion: The long-term outcome of surgically treated patients with LCs is favourable. Age, histopathological type and ipsilateral mediastinal subcarinal lymph node status at baseline were independent prognostic factors for survival and disease recurrence or progression. The extent of surgery and operative macro-radicality also had an impact on prognosis. None of the IHC markers tested appeared to be associated with disease prognosis.

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Section: Discussionmentioning

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lung Carcinoids: Long-Term Surgical Results and the Lack of Prognostic Value of Somatostatin Receptors and Other Novel Immunohistochemical Markers

Daskalakis¹,

Kaltsas²,

Öberg³

et al. 2018

Neuroendocrinology

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“…Although OR51E1 and OR51E2 are ubiquitously expressed in various types of normal and cancerous tissues in humans [28–31], they are significantly more abundant in the healthy human prostate [28]. Both GPCRs belong to the largest subgroup in the mammalian genome, the olfactory receptor (OR) multigene family.…”

Section: Introductionmentioning

confidence: 99%

The activation of OR51E1 causes growth suppression of human prostate cancer cells

et al. 2016

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The development of prostate cancer (PCa) is regulated by the androgen-dependent activity of the androgen receptor (AR). Androgen-deprivation therapy (ADT) is therefore the gold standard treatment to suppress malignant progression of PCa. Nevertheless, due to the development of castration resistance, recurrence of disease after initial response to ADT is a major obstacle to successful treatment. As G-protein coupled receptors play a fundamental role in PCa physiology, they might represent promising alternative or combinatorial targets for advanced diseases. Here, we verified gene expression of the olfactory receptors (ORs) OR51E1 [prostate-specific G-protein coupled receptor 2 (PSGR2)] and OR51E2 (PSGR) in human PCa tissue by RNA-Seq analysis and RT-PCR and elucidated the subcellular localization of both receptor proteins in human prostate tissue. The OR51E1 agonist nonanoic acid (NA) leads to the phosphorylation of various protein kinases and growth suppression of the PCa cell line LNCaP. Furthermore, treatment with NA causes reduction of androgen-mediated AR target gene expression. Interestingly, NA induces cellular senescence, which coincides with reduced E2F1 mRNA levels. In contrast, treatment with the structurally related compound 1-nonanol or the OR2AG1 agonist amyl butyrate, neither of which activates OR51E1, did not lead to reduced cell growth or an induction of cellular senescence. However, decanoic acid, another OR51E1 agonist, also induces cellular senescence. Thus, our results suggest the involvement of OR51E1 in growth processes of PCa cells and its impact on AR-mediated signaling. These findings provide novel evidences to support the functional importance of ORs in PCa pathogenesis.

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“…To date, only a limited number of studies have demonstrated the expression of SSTR subtypes other than SSTR2A in NETs with divergent results, possibly due to differences in the methodology applied [8,9,10,11,12,13,14,15,16,17,18]. Data concerning LCs are even more sparse and inconsistent [15,18,19,20,21,22,23]. Among the five subtypes of SSTRs, SSTR2A is the one most frequently expressed, exhibiting mainly membranous immunostaining, while the other subtypes present mainly cytoplasmic expression [24].…”

Section: Introductionmentioning

confidence: 99%

Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role

Kanakis

Grimelius²,

Spathis

et al. 2015

Neuroendocrinology

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Objective: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). Methods: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. Results: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. Conclusions: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.

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Olfactory receptor 51E1 as a novel target for diagnosis in somatostatin receptor-negative lung carcinoids

Cited by 42 publications

References 26 publications

Lung Carcinoids: Long-Term Surgical Results and the Lack of Prognostic Value of Somatostatin Receptors and Other Novel Immunohistochemical Markers

Lung Carcinoids: Long-Term Surgical Results and the Lack of Prognostic Value of Somatostatin Receptors and Other Novel Immunohistochemical Markers

The activation of OR51E1 causes growth suppression of human prostate cancer cells

Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role

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