| Title | Clinical significance of tumor somatostatin receptor subtype expression | |
| Authors | Aristides Lytras and George Tolis
University of Athens Medical School, Hippokration General Hospital, Endocrine Division, Athens, Greece |
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| Citation | Lytras, A., Tolis, G.: Clinical significance of tumor somatostatin receptor subtype expression, Epitheorese Klin. Farmakol. Farmakokinet. 11(1): 3-12 (1997) | |
| Publication Date | Accepted for publication: 10 April 1997 | |
| Full Text Language | English | |
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| Keywords | Review, somatostatin, somatostatin receptor, somatostatin receptor subtypes, somatostatin receptor scintigraphy, neuroendocrine tumor, cancer, carcinoid, pancreatic cancer, pituitary tumors, endocrine gastroenteropancreatic tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas, small ceil lung carcinomas, lymphomas, brain tumors, meningiomas, astrocytomas, renal cancer, breast tumors, mammary tumors, lung tumors, colorectal cancer, mRNA analysis, RT-PCR. | |
| Other Terms | review article | |
| Summary | Targeting, in a selective mode, at distinct components of tumor growth such as hypersecretion, cell proliferation and angiogenesis, improves clinical responsiveness and minimizes side effects of putative therapeutic approaches. Somatostatin (SS) is a cyclic tetradecapeptide hormone widely expressed in the brain and in the periphery in two main forms, SS-14 and SS-28. Somatostatin receptors (SSTRs) are present throughout the body and SS regulates endocrine and exocrine secretion, cell proliferation and angiogenesis. Octreotide (SMS 201-995, sandostatin) a short SS analogue with increased duration of action compared to SS and has facilitated the clinical application of SS. Somatostatin exerts its multiple effects interacting with at least five distinct 7-transmembrane G-protein- coupled receptor subtypes (SSTR1-5). The SSTR1-5 genes are spread in chromosomes 14, 17, 22, 20 and 16 respectively. AH subtypes interact with SS-14, SS-28 with high affinity. However, based on sequence homologies and interaction with the available short SS analogues such as octreotide, MK-678 or RC-160, two classes of receptor subtypes can be distinguished: The SSTR2/SSTR3/SSTR5 class (sharing 80-96% sequence similarities in certain regions) that interact (high or intermediate affinity) with short SS analogues and the SSTR1/SSTR4 class (sharing 72-82% sequence similarities) that do not interact with short SS analogues. Initial receptor binding studies had documented the presence of SSTRs in most hormone-secreting neuroendocrine tumors [GH and TSH producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTC) and small cell lung carcinomas (SCLC)], in many malignant lymphomas, in several brain tumors (ail meningiomas, most astrocytomas) in renal cell cancers and in breast tumors. A minority of tumors (ovarian tumors, MTC, insulinomas) express SSTRs with low affinity for octreotide.The administration of radiolabeled SS analogues and SSTR scintigraphy represents a new diagnostic approach. [111In-DTPA -phe1]-octreotide (111In-octreotide) was developed for gamma camera imaging of SSTR-positive malignancies. Primary tumors as well as metastases previously unrecognized, can be detected. Thus, visualization of SSTR-positive tumors is widely used in tumor staging and may also predict therapeutic response to octreotide. Tumors that secrete growth hormone or thyroid-stimulating hormone and non-functioning pituitary adenomas, islet cell tumors, carcinoids, paragangliomas, pheochromo- cytofnas, MTC and SCLC are visualized in 70-100% of cases. In a great variety of tumors, particularly of neuroendocrine origin, somatostatin receptors appear to be functional and somatostatin analogues improve the quality of life and may also increase survival for patients bearing tumors that produce peptide hormones which result in clinical syndromes such as carcinoid, Zollinger-Ellison or hypoglycemic syndromes. Successful control of hormonal hypersecretion by pituitary adenomas, metastatic islet cell tumors and carcinoids can be achieved during treatment with SS analogues. The range of malignancies susceptible to octreotide and related SS analogues includes mammary, pancreatic, colorectal and lung tumors. A number of studies have suggested that SSTR scintigraphy (111In-octreotide) can be used to select patients with malignant carcinoid tumors suitable for SS analogue treatment and exclude those that will not benefit from such medication since most hormone-secreting tumors react in vitro to octreotide with an inhibition of hormone release and possibly inhibition of growth. However, octreotide scintigraphy alone may not be sufficient in determining the patients with neuroendocrine tumors who can benefit from chronic treatment with SS analogues, because almost 20% of patients with pathological SSTR scintigraphy fail to respond to such treatment and further, in rare cases, octreotide treatment results in clinical improvement in spite of octreotide scintigraphy failure to demonstrate any tumor localization. The cloning of five human SSTR subtypes (SSTR1-SSTR5) allows the identification of individual SSTR subtypes in various tumors using northern blotting, RT-PCR and in situ hybridization approaches Such approaches identify SSTR2 as the most highly expressed subtype in cases of tumors with positive SSTR scintigraphy. In the few cases of tumors having SSTRs with low affinity for octreotide preferential expression of SSTR1 mRNA has been reported. Further, in carcinoid and giucagonoma patients, SSTR subtyping studies using mRNA analysis have linked SS analogue responsiveness to SSTR2 subtype expression regardless of whether they had a positive or negative scintigraphy. Interestingly, several researchers have reported that, in contrast to the normal pancreatic tissue, many human pancreatic tumors, particularly exocrine pancreatic carcinomas are devoid of SSTR2 a fact likely explaining the poor rate of pancreatic cancer responsiveness to SS analogue treatment. Similar results have been obtained for colorectal cancer. These considerations suggest that in spite of the documented presence of SSTRs by scintigraphy, subtyping of SSTRs should be carried out before considering a SS analogue treatment particularly in patients with pancreatic and colorectal cancer. | |
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