Incidence of Somatostatin Receptors in Human Tumors

Pituitary Adenomas

The normal human anterior pituitary gland is found to express all subtypes of sst receptors, except sst2B and sst4. However, the latter subtype is detectable in fetal pituitary tissue.1 In pituitary adenomas the all subtypes are detectable at least in some cases, depending on the hormone phenotype of the tumors. GH-secreting adenomas expressed mostly sst2 (the distinction between sst2A and sst2B was not done in majority of studies) and sst51-4 (Fig. 1A). The data on sst1 and sst3 are variable from study to study, while sst4 subtype was not detected except for one study.1 The majority of prolactinomas expresses sst1, sst2, and sst5, in approximatively one third of cases sst3 subtype was also detectable, while the expression of sst4 is very rare. In TSH-secreting adenoma all subtypes of sst receptors were found except sst2B.1 The ACTH-secreting adenomas in patients with Cushing's disease sst2 and sst5 are present in majority of cases; sst1 and sst3 are less frequent (a half and one third of cases, respectively) and sst4 expression is exceptional. Recently, the importance of sst5 subtype in ACTH-secreting tumors is underlined. Subtypes sst2 and sst5 have different sensitivity to glucocorticoids, which down-regulate sst2 but not sst5 receptors. The above findings could explain the stronger inhibitory effect of SOM230, a SST analog having a higher affinity to sst5 subtype, in comparison to octreotide.5 The nonfunctioning pituitary adenomas (NFPA) can express all subtypes of sst receptors. As in the other types of adenomas, the expression of sst4 is scarce. The remaining subtypes were found to be more abundant, but the data reported by different authors are not fully concordant.1-4 Our own observations indicate that the dominating subtypes in NFPA are sst5 and sst2B, which are present in all the adenomas examined.6 (Fig. 1B,C). Although NFPA represent the heterogenous group in respect to the expression of pituitary hormones or their subunits and only 1/5 of them are truly hormonally inactive, the only difference between the true inactive (null cell adenomas) and gonadotropin-expressing tumors concerned the appearance of sst4, which was more frequent in the former.6 To summarize, pituitary adenomas frequently express sst receptors. The above constitutes a rationale to the application of SST analogs in order to suppress the pituitary hormone excess in case of functioning tumors and the growth inhibition of both functioning and nonfunctioning tumors. However, the treatment with SST analogs (octreotide and lanreotide) is a routine procedure only in the therapy of GH-secreting pituitary adenomas in patients suffering from acromegaly and of TSH-secreting pituitary adenomas (see Chapter 5 in this book). The trials of SST analogs in the treatment of the other types of pituitary adenomas are in progress, but the results are either controversial or limited in number.7,8 Because the pituitary adenomas express often the subtypes of sst receptors different from sst2 (sst1, 3 and 5) we can lay some hope in the introduction to the routine therapy SST analogs acting on the above-mentioned receptors, e.g. SOM 230.

Colony Forming Ells

Figure 1. A) GH-secreting pituitary adenoma in the patient suffering from acromegaly. Immunostaining with anti-sst2A antibody (SS-800). The membranous localization of the immunoreaction. Reproduced from Pawlikowski M, Endokrynologia Polska 2005; 56:4-5, with permission of the editor. B) FSH/LH-secreting pituitary adenoma immunostained with anti-sst5 antibody (SS-890). C) Alpha-subunit -secreting pituitary adenoma immunostained with the anti-sst2B antibody (SS-860). B and C reproduced from Pawlikowski M et al. Endocrine Pathology 2003; 14:231-238, with permission of the editor. D) Neuroendocrine pancreatic cancer immunostained with anti-sst2A antibody (SS-800). Reproduced from Kunert-Radek J et al. Endokrynologia Polska Pol J Endocrinol 2004; 55:190-195, with permission of the editor. E) Neuroendocrine tumor (carcinoid) immunostained with anti-sst 5 antibody (SS-890). Positive immunostaining in the tumoral cells and vascular endothelia. F) Pheochromocytoma, metastasis to the liver. Strong immunostaining with the anti-sst3 antibody (SS-850).

Figure 1. A) GH-secreting pituitary adenoma in the patient suffering from acromegaly. Immunostaining with anti-sst2A antibody (SS-800). The membranous localization of the immunoreaction. Reproduced from Pawlikowski M, Endokrynologia Polska 2005; 56:4-5, with permission of the editor. B) FSH/LH-secreting pituitary adenoma immunostained with anti-sst5 antibody (SS-890). C) Alpha-subunit -secreting pituitary adenoma immunostained with the anti-sst2B antibody (SS-860). B and C reproduced from Pawlikowski M et al. Endocrine Pathology 2003; 14:231-238, with permission of the editor. D) Neuroendocrine pancreatic cancer immunostained with anti-sst2A antibody (SS-800). Reproduced from Kunert-Radek J et al. Endokrynologia Polska Pol J Endocrinol 2004; 55:190-195, with permission of the editor. E) Neuroendocrine tumor (carcinoid) immunostained with anti-sst 5 antibody (SS-890). Positive immunostaining in the tumoral cells and vascular endothelia. F) Pheochromocytoma, metastasis to the liver. Strong immunostaining with the anti-sst3 antibody (SS-850).

Brain Tumors

High incidence of sst receptors in meningiomas was first reported using the autoradiography with radiolabeled SST and octreotide.9 The more recent data, obtained with RT-PCR, revealed that 88% of investigated meningiomas express at least one of the five sst receptor subtypes. Subtypes sstl and sst2 were the most frequently detected ( 69% and 79%, respectively); sst3, sst4 and sst5 were also present at least in one third of cases.10 Somatostatin receptors are also detected in malignant brain tumors. Fruhwald et al11 reported on immunostaining for sst2 receptors in children brain tumors and found the highest incidence in supratentorial primitive neuroectodermal tumors (7/7) The strong positive immunostaining was also found in 2/3 anaplastic astrocytomas and 2/3 anaplastic ependymomas. On the other hand, the reaction was low in 5 but 1 glioblastomas and 4 but 1 II grade ependymomas. High expression of sst2 receptor subtype is also described in medulloblastomas.12 The data obtained in ex vivo studies do not predict the possibility of demonstration of the tumors in vivo by means of receptor scintigraphy, since the effectiveness of the latter depends also on the functional state of the blood-brain barrier.

Neuroendocrine Tumors

Under the name of neuroendocrine tumors (NET) we mean the tumors deriving from the diffuse neuroendocrine cells localized within the gastrointestinal and bronchial epithelium (former known under the name of APUD system cells). The older name of these tumors was "carcinoids". The endocrine pancreatic tumors are also included in the NET category. The vast majority of these tumors express multiple sst receptors. A lack or weak expression of sst receptors occurrs more often in poorly differentiated NET. The data on the incidence of the particular subtypes of sst receptors in NET are rather concordant. The high incidence of sst2 and rare expression of sst 4 was underlined.13-15 Papotti et al14 have found that in gastrointestinal NET sst1 and sst2 are the subtypes most commonly detected, whereas sst3 and sst5 are expressed by approximatively two-third of cases. Among the hormonally active pancreatic tumors a preferential expression of sst5 was found in "somatostatinomas", sst2 in "gastrinomas" and "glucagonomas", whereas "insulinomas" express all sst receptor subtypes with prevalence of sst2 and sst5.14,16 The nonfunctioning tumors express all subtypes except sst4. 4 The membrane localization of sst2 receptor proteins is prevalent, the other subtypes exhibit often a cytoplasmic or mixed (membrane-cytoplasmic) localization (Fig. 1D,E). Our own unpublished preliminary results concern the immunohistochemical detection of sst1-5 in the neuroendocrine tumors from eight patients. We confirm the high incidence of sst1 (6/8), sst2A (5/8), sst3 (4/8), sst5 (5/8). In contrast, the immunostaining for sst4 was negative in all specimens.

Thyroid Tumors

Somatostatin receptors are abundantly expressed in parafollicular (C) cells- derived medullary thyroid cancers (MTC). In the large series of MTC examined by means of immunohis-tochemistry by Papotti expressed at least one sst receptor subtype. Approximatively half of MTC expressed sst1, sst2, sst3 or sst5. The only subtype rarely detected was sst4 (only 4%). In thyrocyte-derived tumors, sst1-5 were not detected by Northern blot analysis in follicular adenomas and papillary cancers but irregularly expressed in Hurthle cell adenomas and Hurthle cells cancers.1 However, the cited authors detected sst2 subtype in all investigated tumors using another technical approach (ribonuclease protection assay). Thus, in contrast to MTC, the incidence of sst receptors in differentiated thyroid cancers is controversial and needs further studies.

Adrenal Tumors

Normal adrenal cortex and medulla possess somatostatin receptors. The receptors are also expressed in the adrenal tumors, both in that of medullar origin (pheochromocytomas) as well as in adrenocortical tumors. The immunohistochemical study of sst1-5 receptors in pheochromocytomas was published by Mundschenk et al.19 The quoted authors found the positive staining for sst3 receptor subtype in 90% of tumors. In contrast, sst2A subtype was expressed only in 25% of tumors. The remaining subtypes were less frequently detected. The more recent data20 confirm the high incidence of sst3 in pheochromocytomas; the immunopositivity for sst1, sst2A and sst5 was revealed in about one third of the investigated tumors. Among the adrenocortical tumors, functioning adenomas manifesting themselves as Conn's syndrome or Cushing's syndrome, all subtypes of sst receptors are expressed. Contrarly, the nonfunctioning cortical adenomas express mainly sst5; sst1, sst2A and sst 3 were found only in one-third of tumors and sst4 was absent. In adrenal carcinomas, about 50% express sst2A and/or sst3.20 It should be underlined that in immunopositive tumors, both adrenocortical and medullar (pheochromocytomas), only a part of tumoral cells was immunostained.

Nonendocrine Cancers

Somatostatin receptors are expressed or even over-expressed also in several nonendocrine cancers. They were revealed, among others, in breast cancer tumor samples and cell lines. The positive immunostaining with sst2A and/or sst2B antibodies was detected in 85% of breast cancer samples.21 Even the higher percent of the investigated samples (98%) expressed sst2 mRNA.22 The remaining subtypes were also identified, either by immunohistochemis-try, or by PCR. The immunopositivity for sst1 were detected in 52% and in 42% for sst3.21 The presence of mRNA for sst1 was detected in 91% of samples, and for sst3, sst4 and sst5, in 96%, 76% and 54% of samples, respectively.22 The expression level of sst2 receptors is higher in cancer tissue than in nonneoplastic surrounding tissues.23 The incidence of sst1, 2 and 4 correlate positively with estrogen receptor levels, and sst2 additionally with progestrone receptors.22,23 Moreover, high level of sst2 negatively correlated with proliferative potential of the tumor as measured by Ki-67 staining and seems to be a marker of better prognosis.23 The data on the incidence of sst receptors in prostate cancers are controversial. Using the receptor autoradiography, Reubi et al 4 have found the binding of radiolabeled SST-28, but not of octreotide, to the prostate cancer tissue. This finding suggests the presence of sst receptor different from sst2. By means of in situ hybridization and receptor autoradiography, the quoted authors revealed a preferential expression of sst using the RT-PCR and immunohistochemical method, demonstrated subtypes sst1, 2 and 3 in both tumoral and nontumoral epithelial cells, whereas sst4 was expressed preferentially in malignant epithelial cells and sst5 was absent. The lung cancers mainly express sst2 (68% of samples examined immunohistochemically). The incidence of other subtypes are scarcer.27 Interestingly, the sst2 expression is not limited to small cell lung cancer (SCLC), which originates from the neuroendocrine cells of bronchial epithelium, but can be revealed also in nonSCLC. Recently, a functional sst2 was found in a nonSCLC cell line, Calu-6.28 Since melanocytes are known to derive from the neural crest, melanoma is also considered as a neuroendocrine cancer. The high incidence of sst receptors was found in these tumors by means of RT-PCR. Ninety-six % of samples expressed sst1, 83% sst2, 61% sst3, 57% sst4 whereas only 9% sst5.29 The immunohistochemical findings are roughly similar.30 However, the data on functional state of these receptors are controversial and the recent study leads to a conclusion that sst receptors in melanoma are not functional.31 The data on somatostatin receptor detection in gastrointestinal cancers are scarce, with exception of neuroendocrine tumors. The latter are well known to express abundantly the somatostatin receptors and are discussed in the paragraph above. In gastric adenocarcinomas, the expression of both sst3 mRNA and protein was found in cancer cells.32 However, the expression was lower than in normal gastric mucosa. In colorectal adenocarcinomas, the overexpression of sst5 was noticed.33,34 Conversely, the expression of sst2, sst3 and sst4 is low. In most nonendocrine pancreatic cancers, the sst receptors are lacking.35,36 This lack is probably important for etiopathogenesis, since sst2 gene transfer to pancreatic cancer cells inhibits their growth.37 In hepatocellular cancers, sst1 and sst2 are mostly expressed, with intermediate expression of sst3 and low of sst4 and sst5.38 However, the detailed studies of the quoted authors did not reveal any antiproliferative or pro-apoptotic effect of selective SST agonists on sst receptors-expressing hepatocellular cancer lines in vitro. Thus, it seems that these receptors are not fucnctional. The next malignant tumor expressing abundantly sst2 subtype receptors is renal cell cancer. The incidence of other subtypes was sst1>sst4>sst3; no data on sst5 were reported.39 The early studies, based on the in vitro receptor autoradiography, suggested the presence of sst receptors (presumably of sst2 subtype) in nonHodgkin and Hodgkin lymphomas.40 The more recent data confirm the expression of sst2 and sst3 by means of RT-PCR, but not by means of immunohistochemistry.4

Clinical Relevance of Somatostatin Receptors Detection

The direct antiproliferative effects of SST analogs as well as the positive effect of sst-receptor-targeted radiotherapy are determined by at least the presence of sst receptors. Some limited therapeutic effect of SST analogs can be achieved also in sst receptors-negative tumors, via growth hormone/insulin-like growth factor inhibition and/or antiangiogenic action. On the other hand, the detection of sst receptors does not predict that they are functional. Several observations reporting the discrepancies between the receptor incidence and therapeutic effects were published.31,38, The above mentioned discrepancies may depend on structural alterations of receptor proteins or on the alteration of the post-receptor events. It seems that the membrane localization of receptor proteins is also necessary for their biological activity, but this question needs further studies. The coexistence of different subtypes of sst receptors could be also relevant, since heterodimerization of sst receptors can change their functional response. Lastly, it is not fully established what is the significance of sst2 splicing variants, sst2A and sst2B. The in vitro experiments done by Alderton et al43 suggest that these two variants mediate the opposite effects on cell growth (sst2A being responsive for the antiproliferative effect). Such a possibility is supported by our recent finding, that the in vitro effect of selective sst2 agonist correlates with sst2A, but not with sst2B expression.44

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