Somatostatin receptor gene expression in neuroblastoma☆
Introduction
Neuroblastoma is a malignant tumor which arises in the peripheral nervous system during early childhood. The malignant cells may be either neuroblasts or Schwann cells, both of which are derivatives of the neural crest [1]. Neuroblastoma tumors have variable outcomes; stage IV-S tumors may spontaneously regress, while stage I tumors differentiate to ganglioneuroma. Stage II and most stage III neuroblastoma tumors can be cured with surgery and chemotherapy, while stage IV tumors are more aggressive, often becoming resistant to chemo- and radiotherapies. Recent investigations suggest that migration of normal Schwann cells into the tumors may contribute to the spontaneous regression and/or maturation of some neuroblastomas [2].
Currently used prognostic indicators in neuroblastoma include Shimada classification [3], MYCN amplification, patient age, and stage [4]. Several laboratories, including our own, have recently investigated the use of neuropeptide levels as prognostic factors in neuroblastoma [5]. Increased plasma levels of NPY have been demonstrated to correlate with a rapidly growing tumor and to predict early relapse [6]. Increased NPY mRNA expression has been demonstrated in stage IVS tumors [7]. Neuropeptides, including NPY, VIP and somatostatin are thought to play a role in neural crest differentiation. Tyrrell and Landis recently studied NPY and VIP in embryonic neurons, where transcriptional repression of peptide gene expression plays a role in the final neuropeptide profile of sympathetic neurons [8]. During embryonic development, NPY and VIP are detected in dividing neuroblasts and in postmitotic neurons of the rat superior cervical and stellate ganglial [8]. High plasma or tumor levels of VIP and somatostatin correlate with neuroblast differentiation and are favorable prognostic indicators [5].
Expression of somatostatin receptors has also been identified as a favorable prognostic indicator in neuroblastoma [9]. Somatostatin receptor (sst) expression has been demonstrated in neuroblastoma tumor tissue by several techniques, including scintigraphy [10], competitive binding to tumor membranes [11], ex vivo autoradiography of excised tumor tissue [12] and in vivo radioreceptor guided surgery [13]. Moertel et al. demonstrated a positive correlation between somatostatin receptor expression and a favorable prognosis; in addition, these investigators observed an inverse correlation between somatostatin receptors and MYCN amplification [12]. Similarly, Chen et al., demonstrated a positive correlation between high affinity binding of 125I-SS14 to tumor membranes, low clinical stage, and survival in children with neuroblastoma [9].
Five genes for somatostatin receptors (sst1–5) have recently been cloned [14], [15], [16], [17], [18], [19]; however, which receptor subtypes are expressed in neuroblastoma has not yet been delineated. Accordingly, our purpose was two-fold, first to analyze the expression of the five receptor subtype genes in neuroblastoma tissue and second to study the effect of expression of specific receptor subtypes on neuroblastoma cell growth in vivo. The results have important implications for the design of diagnostic and therapeutic protocols utilizing somatostatin analogues in neuroblastoma.
Section snippets
Tumor procurement
Human neuroblastoma tumor specimens were obtained through the Cooperative Human Tissue Network (CHTN). Tissues had been obtained at the time of biopsy and frozen to −80°C within 60 min of extraction. All available patient data, including age at diagnosis, sex, site of primary tumor, stage, Shimada classification, DNA analysis for MYCN content, and survival (Table 1) were provided by CHTN in accordance with guidelines established by the National Cancer Institute and the Children’s Hospital
Somatostatin receptor expression in human neuroblastoma tumors
Thirty-two neuroblastoma tumor specimens were provided by the CHTN (Table 1). The age of patients at diagnosis ranged from 1 day to 8 years. Tumor distribution was 50% adrenal, 19% mediastinal, 12% retroperitoneal, and 6% abdominal which is consistent with the frequency of primary sites in neuroblastoma [4]. Clinical staging is also indicated in Table 1: 50% were stage IV, 28% were stage III, 18% were stages I/II, and 1 patient was stage IV-S. Shimada classification was 41% unfavorable, 19%
Discussion
Our work presents the first molecular analysis of sst expression in human neuroblastoma tumors. We analyzed the expression of the somatostatin peptide gene as well as expression of five somatostatin receptors in 32 tumors from patients with neuroblastoma. All tumors analyzed expressed sst1 while 27/32 expressed sst2.
The lack of expression of sst2 in 16% of the tumor samples analyzed closely approximates the 15% false negative rate of somatostatin receptor based scintigraphy observed in
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Current Status and Future Perspective on Molecular Imaging and Treatment of Neuroblastoma
2023, Seminars in Nuclear MedicineTheranostics in Neuroblastoma
2021, PET ClinicsCitation Excerpt :The use of radiolabeled somatostatin analogs in NB involves a distinct and separate cell surface molecular target, different from the norepinephrine transporter molecule that takes up [131I]MIBG. Somatostatin receptor (SR) scintigraphy has been used for the assessment of NB in the past,51,52 due to its overexpression of SR, mostly types 1 and 2. This rationale has been considered for the development of new PET tracers, such as [68Ga]Ga–DOTA-TOC.52
Non-<sup>18</sup>F-Fluorodeoxyglucos PET Tracers in Pediatric Disease
2020, PET ClinicsCitation Excerpt :Somatostatin receptor (SSTR) imaging has been used widely in diagnosis and treatment of neuroendocrine tumors.75 SSTR, in particular, SSTR1 and SSTR2, was overexpressed in NB cells.76 Although SSTR scintigraphy using non-PET tracers has been used to evaluate NB,77,78 the effect is not as good as with 123I-MIBG.
PET/MR Imaging:: Current Updates on Pediatric Applications
2019, Magnetic Resonance Imaging Clinics of North AmericaCitation Excerpt :These settings, therefore, also could be the indications for combined 18F-FDG PET/MR imaging (Fig. 7), which may be preferred over PET/CT in children. Because somatostatin receptors are expressed in greater than 90% of neuroblastomas,34 radiolabeled somatostatin analogs, such as 68Ga-DOTATATE and 111In-DOTATATE or 177Lu-DOTATATE, may be beneficial for imaging and targeted radionuclide therapy, respectively, in particular for primary refractory or relapsed high-risk neuroblastomas.35,36 The use of other positron-emitting tracers, such as 11C-hydroxyephedrine, 11C-epinephrine, 18F-fluorodopamine, and 18F-DOPA, among others, for the imaging of sympathetic nervous system tumors is still being evaluated.18,19
Redesign of negatively charged <sup>111</sup>In-DTPA-octreotide derivative to reduce renal radioactivity
2017, Nuclear Medicine and BiologyCitation Excerpt :Since neuroendocrine tumors are known to express high levels of somatostatin receptors [1–3], radiolabeled stable analogs of somatostatin such as 111In-DTPA-d-Phe1-octreotide and 90Y–DOTA-Tyr3-octreotide are used clinically for the diagnosis and therapy of neuroendocrine tumors [4–6].
Neuroblastoma: MIBG Imaging and New Tracers
2017, Seminars in Nuclear MedicineCitation Excerpt :Five different types of somatostatin receptors (SSTR) have been discovered so far, and radiolabeled somatostatin analogues have been introduced as an imaging agent for neuroendocrine tumors in the last decade. NB may be characterized by an overexpression of SSTR, more precisely SSTR types 1 and 2.91,92 Therefore, 111In-pentetreotide scintigraphy or, more in general, somatostatin receptor scintigraphy (SRS) have been used for the assessment of NB in the past.2,93
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Supported by the Howard Hughes Medical Institute (A.R.A.), NCI ROl-CA64177 (M.S.O.) and ACS (M.S.O.).