Expression of Somatostatin Receptor Type 2A and PTEN in Neuroendocrine Neoplasms Is Associated with Tumor Grade but Not with Site of Origin

Abstract

Neuroendocrine neoplasms (NENs) are derived from endocrine cells in various organs and share common morphological features. This study aimed to clarify whether NENs of different organs are comparable at the molecular pathologic level. We retrospectively collected 99 cases of NENs from gastro-entero-pancreatic, lung, and other organs and reclassified these according to identical criteria. Grade, site, and molecular expression profile including NE markers, Ki-67, p53, somatostatin receptor type 2A (SSTR2A), and phosphatase and tensin homolog (PTEN) were compared. PTEN immunoreactivity was also compared with genomic copy number by fluorescence in situ hybridization (FISH) and droplet digital polymerase chain reaction (ddPCR). No significant differences were observed in the immunoreactivities of NE markers, p53, SSTR2A, or PTEN expression in NENs between the different organ sites. PTEN and p53 functional inactivation along with the loss of membranous SSTR2A expression appeared to be commonly involved in high-grade NEN. FISH results were significantly correlated with the level of PTEN immunoreactivity and with the findings of ddPCR analyses. The demonstration that these tumors are comparable at the molecular level will likely contribute to the broadening of therapeutic options such as the use of somatostatin analogues and mTOR inhibitors against NENs regardless of the affected organ, whereas molecular characterization of tumor grade will be useful for determining treatment strategy.

Large Cell Neuroendocrine Carcinoma Shares Similarity with Small Cell Carcinoma on the Basis of Clinical and Pathological Features

“…Collaud and colleagues revealed that, compared with the carcinoids, the high-grade pulmonary NETs tumors presented a stronger loss of PTEN [11]. Wada and colleagues analyzed the PTEN expression in the NETs of multiple organs and found that PTEN immunoreactivity levels were significantly lower in the high-grade NETs subgroup, while p53 expression were significantly higher in the high-grade NETs subgroup, which was entirely consistent with our results in pulmonary NETs [10]. Our data also revealed that, with the elevation of differentiation grade, p53 expression level gradually increased, but PTEN expression level gradually decreased (Table 3).…”

“…Besides, CD117 as a transmembrane tyrosine kinase receptor (TKR) was reported to be overexpressed in most of the high-grade NETs, which suggested a potential therapy of Imatinib [8], [9]. Moreover, somatostatin receptor 2A/5 (SSR2A/5) and phosphatase and tensin homolog (PTEN) expression levels, which were predictive of sensitivity to somatostatin analog and mammalian target of rapamycin (mTOR) inhibitor treatment, respectively, were reported significantly decreased with tumor grade progression, regardless of the site of tumors [10], [11]. Therefore, we wondered whether some similar phenomena in the expression of these markers could be discovered in pulmonary NETs.…”

Neuroendocrine tumor theranostics

“…Five types of SSTRs have been identified. Somatostatin receptor type 2, especially type 2A, is highly expressed in NETs 13 …”

Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner

“…Thus, a more detailed characterization of the two antagonists in vivo, as carried out in the perfusion studies (17), should be performed. However, the wide expression of SSTR2 argues against antagonism for this receptor for future pharmacological development since this may influence many systems; importantly, the Sstr2 has been found to be highly expressed in certain types of cancers (48)(49)(50). SSTR5, on the other hand, is much more discretely expressed with particularly high expression levels in the GLP-1 secreting L-cells in the gut, hopefully limiting any untoward side effects.…”