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 vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, 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 than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor ß 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. However, 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 checkpoint molecules are heterogeneously expressed in NETs' surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs' microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.