Abstract
Somatostatin analogs mantain their major role in the treatment of patients with advanced neuroendocrine tumors (NETs) and have multiple modulatory effects on the immune system. Here, we evaluated the effects of lanreotide treatment on expression of Th1, Th2 cytokine patterns in serum of patients with NETs and in bronchial and pancreatic NET cell lines. Our results showed that lanreotide treatment promoted a Th1 cytotoxic immune-phenotype in patients with NETs originated by intestinal sites. Similar results were obtained also in vitro where lanreotide induced expression of Th1 cytokines only in pancreatic and not in bronchial-derived NET cell lines. It seems, therefore, that cytokinomics can represent a useful tool for the identification of tumor biomarkers for the early diagnosis and evaluation of the response to therapy in NET patients. To avoid the drug-resistance induced by everolimus (mTOR inhibitor), we made the pancreatic NET cell line resistant to this drug. After treatment with lanreotide we found that the drug reduced its viability compared to that of sensitive cells. These data may have direct implications in design of future translation combination trial on NET patients.
Highlights
Neuroendocrine Neoplasms (NENs) are heterogeneous, with increasing incidence in the last decades arising from altered stem cells programmed to evolve in ultimate lineages scattered with secretory granules and the ability to produce hormones that lead to carcinoid syndrome
Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the so-called “Neuroendocrine Diffuse System” with morphological and functional features similar to neurons, they are without axons or synapses
Both IFN-γ and TNFα were not detectable in patients with mammary and bronchial neuroendocrine tumors (NETs) suggesting that other cytokines such as IL-17A as well as IL-8 might be involved in the activation pathways of these tumors or that their expression may not be modulated by lanreotide for a different expression of sensitive Somatostatin receptor (SSR)
Summary
Neuroendocrine Neoplasms (NENs) are heterogeneous, with increasing incidence in the last decades arising from altered stem cells programmed to evolve in ultimate lineages scattered with secretory granules and the ability to produce hormones (neuropeptidic, neurotransmitter and neuromodulator with endocrine, autocrine and paracrine action) that lead to carcinoid syndrome. Most patients with NETs are diagnosed with advanced diseases and the mortality rate is 50% within five years [3, 4] Their treatment is based upon surgical resection for localized tumors or for NETs with a regional diffusion and, to alleviate the symptoms, in metastatic or high-grade tumors [5, 6]. The receptors can form dimers having complex effects on the cells through the activation of alternative signal transduction pathways [13]. Most of these NETs express SSR, predominantly subtypes 1, 2, and 3 with an inverse correlation with the grade of differentiation of the tumor [14]
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