The Truncated Isoform of Somatostatin Receptor5 (sst5TMD4) Is Associated with Poorly Differentiated Thyroid Cancer

Abstract

Somatostatin receptors (ssts) are expressed in thyroid cancer cells, but their biological significance is not well understood. The aim of this study was to assess ssts in well differentiated (WDTC) and poorly differentiated thyroid cancer (PDTC) by means of imaging and molecular tools and its relationship with the efficacy of somatostatin analog treatment. Thirty-nine cases of thyroid carcinoma were evaluated (20 PDTC and 19 WDTC). Depreotide scintigraphy and mRNA levels of sst-subtypes, including the truncated variant sst5TMD4, were carried out. Depreotide scans were positive in the recurrent tumor in the neck in 6 of 11 (54%) PDTC, and in those with lung metastases in 5/11 cases (45.4%); sst5TMD4 was present in 18/20 (90%) of PDTC, being the most densely expressed sst-subtype, with a 20-fold increase in relation to sst2. In WDTC, sst2 was the most represented, while sst5TMD4 was not found; sst2 was significantly increased in PDTC in comparison to WDTC. Five depreotide positive PDTC received octreotide for 3–6 months in a pilot study with no changes in the size of the lesions in 3 of them, and a significant increase in the pulmonary and cervical lesions in the other 2. All PDTC patients treated with octreotide showed high expression of sst5TMD4. ROC curve analysis demonstrated that only sst5TMD4 discriminates between PDTC and WDTC. We conclude that sst5TMD4 is overexpressed in PDTC and may be involved in the lack of response to somatostatin analogue treatment.

Expression of somatostatin receptor 2A in medullary thyroid carcinoma is associated with lymph node metastasis

“…However, other studies support the thesis of SSTR2A and 5 inducing cell proliferation. Expression of the truncated SSTR5 variant is associated with poorly differentiated papillary and follicular thyroid carcinomas and also with tumour invasiveness in breast cancer and somatotropinomas . In gastrointestinal and bronchopulmonary neuroendocrine neoplasms, an immunohistochemical analysis showed that higher protein expression levels of somatostatin receptor 2 correlated with tumour stage and the tendency to metastasize , which is in concordance with our observations in medullary thyroid carcinomas.…”

The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer

“…In PCa, ssts are expressed and are capable of mediating such functions (5); however, some initial but limited studies that used SSAs reported no benefit in overall survival in patients with PCa (11,26), and the mechanistic reasons of this clinical failure are still unknown. Given that aberrant alternative splicing is a cancer hallmark (13,27) and our group has demonstrated the presence and relevant pathologic function of the spliced sst5TMD4 variant in other cancer types (15,(17)(18)(19)(20), we hypothesized that sst5TMD4 could be present and play a role in the development and/or progression of PCa or in the response to SSAs in PCa.…”

“…In addition, in contrast to the predominant plasma membrane localization of other ssts, sst5TMD4 demonstrates a preferential intracellular localization wherein it may disrupt the function of other ssts, mainly sst2 and sst5 (14). Of more interest, sst5TMD4 is barely expressed in normal tissues but is highly overexpressed in several tumors and cancers, including pituitary adenomas (15,16), breast cancer (17), thyroid carcinoma (18,19), and NETs (20), where it correlates with aggressive clinical parameters and promotes cell proliferation, migration, invasion, and hormone secretion (15,17,19,20). Indeed, sst5TMD4 expression is negatively correlated with the ability of SSAs to reduce growth hormone secretion in pituitary adenomas (16) and inhibits the ability of sst2-transfected cells to respond to SST and/or SSAs (17).…”

Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas

“…As previously reported [12], ROC was performed for evaluation of diagnostic test sensibility and specificity. Specifically, in this study ROC was used as a tool to measure how well the expression of sst5TMD4, sst2 and sst5 could distinguish between the diagnostic groups [patients presenting extension into sinus (total invasion and invasion into cavernous or sphenoid sinus)].…”

“…On a different scenario, we have demonstrated that sst5TMD4 presence is associated with poor prognosis in breast cancer, and its expression in a germane cell model (MCF-7 cell line) increases malignancy features (proliferation, invasiveness and migration) [11]. Similarly, sst5TMD4 presence is associated with poor prognosis in thyroid cancer [12]. …”