Neuroendocrine System

The neuroendocrine system is composed of specialized cells, which combine the properties of neuronal cells that respond to neural stimuli as well as endocrine cells that synthesize and excrete hormones, amines or peptides into the bloodstream (Asa, Rosa, and Mete. 2020). In addition, these cells express specific protein markers such as synaptophysin in the membranes of intra-cytoplasmic small presynaptic-like vesicles or chromogranin A in large dense core hormone granules (Klöppel G. 2017) (Figure 1).

Neuroendocrine cells are distributed throughout the body, including:

• glands such as the pituitary, parathyroids and adrenals

• clusters within glands, such as islet cells in the pancreas secreting insulin and C cells in the thyroid secreting calcitonin

• scattered within the exocrine parenchyma, particularly in the gastrointestinal (GI) and respiratory tracts (Oronsky B et al. 2017)

Classification of Neuroendocrine neoplasms (NENs)

As neuroendocrine cells are distributed throughout the body, neuroendocrine neoplasms (NENs) have been found in the central nervous system, respiratory tract, larynx, gastrointestinal tract, thyroid, skin, breast, and urogenital system. In addition, they are highly variable in morphology, genomic alterations, clinical manifestation and outcomes. Most NENs are classified as well-differentiated neuroendocrine tumors (NETs), comprising 80-90% of all diagnosed NENs. The rarer form of NENs termed Neuroendocrine carcinomas (NECs) are poorly differentiated and more aggressive (Pavel et al. 2020) (Table 1).

The most frequent sites of origin of the neoplasms are the digestive and pancreatic systems (70%), followed by the respiratory tract (25%) (Klöppel G. 2017). Epithelial well-differentiated neoplasms of the digestive and pancreatic systems, comprising tumor cells that retain the morphological and molecular features of their precursor cells, are defined as gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (Rindi G et al. 2022).

SSTRs and somatostatin signaling

Somatostatin is a naturally occurring peptide hormone primarily secreted by the pancreas, gastrointestinal tract, and central nervous system. Somatostatin is involved in inhibiting five somatostatin receptors (SSTR1 to SSTR5), all G-coupled protein receptors (GCPRs), which play roles in numerous metabolic processes related to neurotransmitters and endocrine and exocrine secretions (Eychenne R et al. 2020). Around 80% of NETs overexpress SSTR types 1 and 2 on their cell surface. This makes targeting SSTR a valuable tool for diagnosing, staging, and treating NET patients (Baldelli R et al. 2014). Targeting SSTR signaling in NETs at a functional level with somatostatin analogs (SSAs) inhibits hormonal secretion, cell cycle progression, angiogenesis, and cell migration (Eychenne R et al., 2020) (Figure 2).

SSTR receptors can also be exploited for theranostic approaches, using theranostic pairs for the imaging of tumors and their treatment using targeted radiopharmaceutical therapy.

References:

• Asa, Sylvia L., Stefano La Rosa, and Ozgur Mete. 2020. The Spectrum of Neuroendocrine Neoplasia: A Practical Approach to Diagnosis, Classification and Therapy. Springer Nature. DOI: 10.1007/978-3-030-54391-4

• Klöppel, Günter. 2017. “Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications.” Visceral Medicine 33(5): 324–30. DOI: 10.1159/000481390

• Waldum, Helge L. et al. 2018. “Not Only Stem Cells, but Also Mature Cells, Particularly Neuroendocrine Cells, May Develop into Tumours: Time for a Paradigm Shift.” Therapeutic Advances in Gastroenterology 11: 1756284818775054. DOI: 10.1177/1756284818775054

• Oronsky, Bryan, Patrick C. Ma, Daniel Morgensztern, and Corey A. Carter. 2017. “Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas.” Neoplasia 19(12): 991–1002. DOI: 10.1016/j.neo.2017.09.002

• Pavel, M. et al. 2020. “Gastroenteropancreatic Neuroendocrine Neoplasms: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up.” Annals of Oncology 31(7): 844–60. DOI: 10.1016/j.annonc.2020.03.304

• Rindi, Guido et al. 2022. “Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms.” Endocrine Pathology 33(1): 115–54. DOI: 10.1007/s12022-022-09708-2

• Eychenne, Romain et al. 2020. “Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy.” Molecules, 25(17), Article 17. DOI: 10.3390/molecules25174012

• Baldelli, Roberto et al. 2014. “Somatostatin Analogs Therapy in Gastroenteropancreatic Neuroendocrine Tumors: Current Aspects and New Perspectives.” Frontiers in Endocrinology, 5. DOI: 10.3389/fendo.2014.00007