Expression prevalence and dynamics of GPCR somatostatin receptors 2 and 3 as cancer biomarkers beyond NET: a paired immunohistochemistry approach

Abstract

Somatostatin receptors are clinically validated GPCR biomarkers for diagnosis and treatment of various neuroendocrine tumors (NET). Among the five somatostatin receptors, SST2 and SST3 are associated with apoptosis and cell cycle arrest, making these receptor subtypes better differentiated targets in precision oncology. In this study we performed immunohistochemistry of paired tissue microarrays containing 1125 cores, representing 43 tumor types, each stained for SST2 and SST3. A 12-point immunoreactive scoring (IRS) range was used for interpretation of the staining results. We analyzed the results twice, using the conventional positivity IRS cutoffs ≥ 3 and more stringent ≥ 6. Evaluation of receptors expression dynamics was performed for tumor-nodes-metastases (TNM) defined subgroups (ovarian and hepatocellular adenocarcinomas) as a function of their tumor stage. Our results indicate that two-thirds of tested cores exhibit clinically significant expression of at least SST2 or SST3 (IRS ≥ 6). The expression prevalence of both receptors tends to decline with tumor progression. However, an unexpected upregulation of both SST2 and SST3 reemerged in metastases suggesting conserved receptors genetic potential during tumor life cycle. We suggest that SST2 and SST3 should be further explored as potential biomarkers and therapeutic tools for maximizing the efficiency of somatostatin-based precision oncology of solid tumors beyond NET.

Figure 1

Distribution of positive expression of SST2A and SST3 in the tested cohort as detected by IRS conventional interpretation (≥ 3) and clinically relevant (≥ 6) method. The pane below presents methods of interpretation of IRS results as used today.

Figure 2

Prevalence of SST2A and SST3 expression in selected indications, by IRS ≥ 6, ordered from most expressing (top left) to least expressing (bottom right): Blue—% samples expressing SST2A only; Yellow—% samples expressing SST3 only; Orange—% samples expressing both SST2A and SST3; Grey—% samples not expressing SST2A or SST3.

Figure 3

Relationship between SST2A expression intensity and tumor T (TNM) in ovarian carcinomas (left) and hepatocellular carcinomas (right). SST2 IRS individual values distribution of 38 ovarian carcinoma tissues (T1: n = 28, T2: n = 6, T3: n = 4) and 167 HCC tissues (T1: n = 3, T2: n = 49; T3: n = 110; T4 = 5) are presented as black dots. Upper and lower quartiles, median and outlier values (> quartile 3 + 1.5 × interquartile range) are depicted in red. By GraphPad Prism 10.0.3 (275).

Figure 4

IRS of SST2A expression in the tested specimens, as percentile of the tested core numbers. Indications represented by more than 6 cores are shown.

Figure 5

IRS of SST3 expression in the tested specimens, as percentile of the tested core numbers. Indications represented by more than 6 cores are shown.