The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications

Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross-talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including VEGF, PDGF, FGF, semaphorins and angiopoietins, that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher then epithelial tumors. Also, NETs operate multi-faceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, CTGF and TGF- β primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely major complications of functioning NETs. Ho wever, at present little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoi nt molecules are heterogen...
Source: Neuroendocrinology - Category: Endocrinology Source Type: research