SSTR-2 as a potential tumour-specific marker for fluorescence-guided meningioma surgery

Abstract

BackgroundMeningiomas are the most frequently occurring primary intracranial tumours in adults. Surgical removal can only be curative by complete resection; however surgical access can be challenging due to anatomical localization and local invasion of bone and soft tissues. Several intraoperative techniques have been tried to improve surgical resection, including intraoperative fluorescence guided imaging; however, no meningioma-specific (fluorescent) targeting has been developed yet. Here, we aimed to identify the most promising biomarkers for targeted intra-operative fluorescence guided meningioma surgery.MethodsOne hundred forty-eight meningioma specimens representing all meningioma grades were analysed using immunohistochemistry (IHC) on tissue microarrays (TMAs) to determine expression patterns of meningioma biomarkers epithelial membrane antigen (EMA), platelet-derived growth factor β (PDGF-β), vascular endothelial growth factor α (VEGF-α), and somatostatin receptor type 2 (SSTR-2). Subsequently, the most promising biomarker was selected based on TArget Selection Criteria (TASC). Marker expression was examined by IHC in 3D cell culture models generated from freshly resected tumour material.ResultsTMA-IHC showed strongest staining for SSTR-2. All cases were positive, with 51.4% strong/diffuse, 30.4% moderate/diffuse and only 18.2% focal/weak staining patterns. All tested biomarkers showed at least weak positivity in all meningiomas, regardless of WHO grade. TASC analysis showed that SSTR-2 was the most promising target for fluorescence guided imaging, with a total score of 21 (out of 22). SSTR-2 expression was determined on original patient tumours and 3D cultures of three established cultures.ConclusionsSSTR-2 expression was highly sensitive and specific in all 148 meningiomas, regardless of WHO grade. According to TASC analysis, SSTR-2 is the most promising receptor for meningioma targeting. After establishing in vitro meningioma models, SSTR-2 cell membrane expression was confirmed in two of three meningioma cultures as well. This indicates that specific fluorescence in an experimental setting can be performed for the further development of targeted fluorescence guided meningioma surgery and near-infrared fluorescent tracers targeting SSTR-2.

Evaluation of Ac-Lys0(IRDye800CW)Tyr3-octreotate as a novel tracer for SSTR2-targeted molecular fluorescence guided surgery in meningioma

“…After incubation with 800CW-TATE, the tumor bulk fluoresced, whereas the dura did not (c). SSTR 2 expression determined by IHC showed a strong membranous expression in the tumor bulk, but was absent in the dura mater, in concordance with tracer fluorescence (b, right panel; c) ◂ available in literature and our previous results where we found no significant differences in SSTR 2 -expression among WHO grades [7][8][9][10][11]. Nevertheless, the current results illustrate that 800CW-TATE binds to all meningioma grades.…”

“…The meningioma Fig. 2 [7]. Incubation with 800CW-TATE showed fluorescence in all meningioma samples with membranous and cytoplasmic staining patterns.…”

“…Separate consecutive FFPE sections of tissue obtained from animal studies were used for staining with either 4′,6-diamidino-2-phenylindole (DAPI), hematoxylin and eosin (H&E), or SSTR 2 expression analysis (AC-0162RUO, SanBio) [ 7 ].…”

“…In the present study, we developed a possible tracer for meningiomas that is directed against the somatostatin receptor subtype 2 (SSTR 2 ). We and others previously demonstrated overexpression of SSTR 2 on all meningioma grades, making it a promising biomarker for binding [6][7][8][9][10][11]. Tyr 3 -octreotate, a previously generated peptideanalogue with a high affinity for SSTR 2 [12], served as the meningioma specific binding part.…”

Clinical Significance of Somatostatin Receptor (SSTR) 2 in Meningioma

“…For instance, SSTR2 was identified as significantly highly expressed in meningioma tissues compared with normal tissues by Anne et al (26). The expression of SSTR2 can routinely be detected through reverse-transcription polymerase chain reaction and immunohistochemistry (Table 1); the vast majority of meningiomas express SSTR2 (14,(25)(26)(27)(28)(29)(30)(31)(32). SSTR2 mediates diverse physiological effects when activated by somatostatin or its synthetic analogs, such as regulating the physiologic secretion of insulin, glucagon, thyroid-stimulating hormone, and growth hormone (GH); protecting retina nerves; and regulating neuronal excitability (13,23,(33)(34)(35)(36).…”