Somatostatin Receptor Subtypes in Human Pheochromocytoma: Subcellular Expression Pattern and Functional Relevance for Octreotide Scintigraphy

Abstract

The stable somatostatin analog octreotide has been successfully used for imaging and treatment of a variety of human tumors. In pheochromocytoma, data on somatostatin receptor subtyping have thus far been sparse. Pheochromocytomas often express more than one somatostatin receptor, and it is uncertain by which receptor subtype the functional responses of octreotide are mediated. Here, we have examined somatostatin receptor protein expression in a panel of 52 pheochromocytomas from 35 randomly selected patients by immunostaining with specific polyclonal anti-sst(1-5) and monoclonal mouse anti-SS-14 antibodies. Staining pattern, distribution and subcellular localization of somatostatin receptor subtypes were investigated. Seventeen patients received (111)In-octreotide scintigraphy. Although the vast majority of tumors (90%) showed positive immunohistochemical staining for sst(3), immunoreactive sst(2A) receptors were only seen in 13 tumors (25%). All other somatostatin receptor subtypes were less frequently detected. Interestingly, among sst(3)-positive tumors strikingly different subcellular distributions of immunoreactive sst(3) receptors were observed. In most cases, immunoreactive sst(3) receptors were distributed throughout the cytosol. Scintigraphic localization of tumors larger than 1 cm in diameter was always successful in the presence of immunoreactive sst(2A) receptors. In the absence of sst(2A), true-positive octreotide scintigraphy was only seen in the presence of membrane-associated sst(3) immunoreactivity. Our findings suggest that selective expression of functional membrane-associated sst(3) receptors is sufficient for high tracer uptake during octreotide scintigraphy in a subgroup of human pheochromocytomas. These tumors may represent a potential target treatment with somatostatin receptor agonists with improved sst(3) activity.

Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy

“…23 Among alternative methods, immunohistochemistry seems to be a reliable tool to detect the somatostatin receptor profile in neuroendocrine tumors, due to the following advantages: detection of the receptor protein (instead of RNA, for example in PCR-based methods), possibility of detecting the cellular type expressing the receptor (neoplastic cells vs blood vessels or reactive lymphocytes, etc), availability of subtype specific antibodies, applicability in archival material, low cost/benefit ratio which renders this method applicable in most laboratories. 13,[15][16][17]19,21 On the contrary, major disadvantages are related to the lack of standardization of the method (from both technical and interpretation viewpoints) which is a great limitation in diagnostic applications, the failure of demonstrating 'functional' receptors (as opposed to autoradiography), and undetermined sensitivity of the technique, since limited evidence has been reported on the correlation between immunohistochemistry and other in vivo techniques. In a recent paper, Korner et al 15 tested different somatostatin receptor type 2A antibodies in different human tumors, and correlated the immunohistochemical pattern with previous autoradiographic data on 37 cases, demonstrating a good correlation between the two methods applying the same antibody selected in our study.…”

“…Several studies have documented that generally these methods correlate each other in somatostatin receptors positive cases, with only minor discrepancies. [13][14][15][16][17][18][19][20][21][22] The currently available somatostatin analogues bind preferentially somatostatin receptors type 2 (which is the most widely expressed subtype in neuroendocrine tumors) and to a lower extent types 3 and 5, and somatostatin receptors profiling in individual patients may be of relevance to better tailor the somatostatin analogue-based treatment. This would hopefully allow to increase the response rate of each patient and reduce costs of biotherapy, which are generally high.…”

Radiolabeled somatostatin receptor antagonists are preferable to agonists forin vivopeptide receptor targeting of tumors

“…First, after safety and efficacy evaluation in humans, radiolabeled DOTA-sst 3 -ODN-8 should be evaluated in patients with sst 3 -expressing tumors, such as inactive pituitary adenomas or pheochromocytomas (24,25). Radiolabeled DOTA-sst 2 -ANT should be studied in patients with sst 2 -expressing tumors, consisting of a majority of neuroendocrine tumors.…”

The role of somatostatin and dopamine D2 receptors in endocrine tumors

“…The catecholamine-producing and -secreting tumor pheochromocytoma has been shown to express SS (Reubi et al 1992c) and more than one SSTR receptor both at mRNA and protein level (Reubi et al 1992c, Kubota et al 1994, Mundschenk et al 2003, Kolby et al 2006, being the subtypes 1-3 the most represented (Hofland & Lamberts 2003, Unger et al 2004. Similarly, in vivo and in vitro studies on medullary thyroid carcinomas detected the presence of all sst subtypes, except sst 4 , and showed a clear positivity for SS, indicating that possible autocrine/ paracrine circuits may be active in this tumor (Pacini et al 1991, Kwekkeboom et al 1993, Mato et al 1998, Papotti et al 2001b, Zatelli et al 2006).…”