Distribution of somatostatin receptors in normal and tumor tissue
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Somatostatin-14 and somatostatin-28 are derived from the same peptide, prosomatostatin by the post-translational modification and make a somatostatin family. Recent advance in molecular biology has revealed that somatostatin receptors also constitute a family of structurally-related proteins. The members of the somatostatin receptor family are SSTR1-5, which have different expression pattern, pharmacological characterization and coupling with intracellular second messenger systems. Efficacy of SMS 201-995, a clinically available somatostatin analog, against endocrine tumors seems to be correlated with expression of SSTR2 which has a high affinity for SMS 201-995. Cloning of somatostatin receptors will further facilitate development and application of somatostatin analogs in diagnosis and treatment of tumors.
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Somatostatin blocks the release of numerous growth factors and is therefore a potent inhibitor of cell division and/or secretion. It exerts its effects through binding to somatostatin receptors. Five different subtypes of such receptors are identified (SSTR1 to SSTR5), having various tissue expression. The detection of their presence in tumours can be performed on histological sections and has potential therapeutic implications.
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Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been a large subject of interest in the discovery of potential biomarkers and treatment options for the disease. The aim of this review is to describe the molecular characteristics of somatostatin and somatostatin receptors and its application in diagnosis and therapy on patients with NENs as well as the use in the near future of somatostatin antagonists.
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Most neuroendocrine tumors express receptors for somatostatin which was originally isolated as a hormone with growth hormone releasing inhibiting potential. The molecular cloning of five receptor subtypes for somatostatin has expanded our knowledge on the actions of this peptide. We studied the expression of all five somatostatin receptor subtypes in various normal human tissues and a variety of endocrine tumors. Different quantitative expression rates in normal tissues were identified by realtime RT-PCR. Expression in these tissues was confirmed by immunohistochemical analysis. We then compared the physiological expression to the somatostatin receptor expression in tumors arising from the same tissue. Our investigation of pituitary adenomas revealed that somatostatin receptor subtypes are not only expressed in GH-producing adenomas but also in ACTH-producing adenomas and prolactinomas as well as in non-functioning pituitary adenomas. Further analysis of other endocrine tumors demonstrated expression in pheochromocytomas as well as in tumors of the adrenal cortex with tumor-specific distribution pattern. This may offer new diagnostic and therapeutic possibilities with multiligand or subtype specific somatostatin analogs. Somatostatin analogues are very effective in the treatment of symptoms related to endocrine tumors. New analogues like the multi-ligand SOM230 are currently studied in phase 2 studies. The high expression of somatostatin receptors is used to localize endocrine tumors by receptor szintigraphy with radiolabeled somatostatin analogues. Tumor-targeted radioactive treatment based on somatostatin analogues is currently evaluated as a treatment option.
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In the past year, there have been major advances in our understanding of the mechanisms of action of somatostatin. The cloning and characterizing of genes encoding five structurally similar somatostatin receptors and their transfection into cells have allowed identification of analogues that are receptor-subtype specific. There is now a significant opportunity for the development of somatostatin analogues that are targeted more specifically to the individual tissue or hormone that is in excess. Work continues to demonstrate the antiproliferative action of somatostatin on tumor cells; however, there have been examples of tumor cell-line proliferation in response to somatostatin. This highlights the need for caution in the use of somatostatin analogues as adjuncts to other chemotherapeutic agents, even in somatostatin receptor-positive tumors. The role of; somatostatin in the diagnosis of neuroendocrine tumors is to define the position and extent, and studies continue to support its role in this area. It is the functional characterization of the receptor genes, however, that represents the most significant advance. This characterization may change somatostatin-analogue therapy from its current use as a general endocrine “off switch” to a more targeted treatment that is used only when the receptor-subtype status of the tumor has been established. In this setting, somatostatin analogues may rank among the most specific therapeutic agents at our disposal.
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The neuropeptide somatostatin is widely distributed in the central nervous system and in peripheral tissues and may be involved in the regulation of a number of physiological functions including movement and cognition. Somatostatin may also have a role in the development of the central nervous system, in particular, the cerebellum and spinal cord. Somatostatin induces its actions by interacting with a family of membrane associated receptors. Recently, five somatostatin receptors have been cloned and referred to as SSTR1-SSTR5. The distribution of the expression of the mRNAs for these receptors are distinct but overlapping. Preliminary pharmacological analysis of these receptors may lead to the development of selective ligands at these receptors. These compounds may be useful in identifying the selective functions of these receptor subtypes. Some somatostatin analogues have antiproliferative actions and are used presently to treat carcinoids. Development of subtype selective somatostatin analogues could be helpful in further identifying somatostatin receptor-expressing tumors and in the treatment of cancer. The cloning of these receptors has now opened up the possibility of more clearly investigating the functions of somatostatin in the brain and peripheral tissues and will facilitate the generation of new somatostatin drugs that may be employed for the treatment of a number of diseases.
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Partial table of contents: Regulation of Somatostatin Gene Transcription by cAMP (M. Montminy, et al.). Processing and Intracellular Targeting of Prosomatostatin-Derived Peptides: The Role of Mammalian Endoproteases (Y. Patel & A. Galanopoulou). Molecular Biology of Somatostatin Receptors (G. Bell, et al.). Characterization of Somatostatin Receptor Subtypes (Ch. Bruns, et al.). Regulation of Somatostatin Receptor mRNA Expression (M. Berelowitz, et al.). Transient Expression of Somatostatin Receptors in the Brain During Development (P. Leroux, et al.). Interaction of Somatostatin Receptors with G Proteins and Cellular Effector Systems (T. Reisine, et al.). Function and Regulation of Somatostatin Receptor Subtypes (A. Schonbrunn, et al.). Appendix. Indexes.
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