Sprouting strategies and dead ends in anti-angiogenic targeting of NETs

Abstract

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that arise from cells of the neuroendocrine system. NETs are characterized by being highly vascularized tumors that produce large amounts of proangiogenic factors. Due to their complexity and heterogeneity, progress in the development of successful therapeutic approaches has been limited. For instance, standard chemotherapy-based therapies have proven to be poorly selective for tumor cells and toxic for normal tissues. Considering the urge to develop an efficient therapy to treat NET patients, vascular targeting has been proposed as a new approach to block tumor growth. This review provides an update of the mechanisms regulating different components of vessels and their contribution to tumor progression in order to develop new therapeutic drugs. Following the description of classical anti-angiogenic therapies that target VEGF pathway, new angiogenic targets such as PDGFs, EGFs, FGFs and semaphorins are further explored. Based on recent research in the field, the combination of therapies that target multiple and different components of vessel formation would be the best approach to specifically target NETs and inhibit tumor growth.

Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors

“…Sunitinib is the only targeted therapy approved for pNETs, and relapse after an initial response. Carrasco et al, recently reviewed classical antiangiogenic therapies, and discussed some new angiogenic targets in NETs [210]. Here, we summarize some novel antiangiogenic “drug” molecules/agents, which may be promising and potential therapeutic targets in pNETs (Table 1).…”

Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications

“…Moreover, this vascularization provides an access to the bloodstream that the tumor uses to metastasize. This is true for almost all malignancies, including NETs (7). Angiogenesis is tightly regulated by a complex balance between pro-and anti-angiogenic molecules, and a cross-talk exists between endothelial cells, pericytes and tumor cells.…”

“…Mounting evidence indicates that semaphorins and angiopoietins contribute to neoangiogenesis in NETs. Semaphorins have shown both pro-and anti-angiogenic effects in NETs, and their activity is the result of the interaction with neuropilin and plexin receptors (7). Neuropilin receptors have been found in both pancreatic, intestinal and pulmonary NETs (39)(40)(41), while data on the expression of plexin receptors in NETs Schematic overview of the main pathways regulating angiogenesis in NETs.…”

“…Neuroendocrine tumors are highly vascularized malignancies, and their intratumor vessel density is estimated to be approximately 10-fold higher than in carcinomas ( 6 , 7 ). This feature is not particularly surprising, as it recapitulates the microscopic architecture of normal endocrine glands which are characterized by a dense vascular network facilitating hormone secretion.…”

Clinical and Preclinical Advances in Gastroenteropancreatic Neuroendocrine Tumor Therapy

“…Neuroendocrine tumors are highly vascular tumors and overexpression of proangiogenic molecules and their receptors such as vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), platelet-derived growth factor (PDGF)/PDGFR, fibroblast growth factor (FGF)/FGFR, and epithelial growth factor (EGF)/EGFR have been reported ( 55 , 56 ). These observations have led to extensive preclinical and clinical investigations using tyrosine kinase inhibitors (TKI; either small molecule antagonists or blocking antibodies) that inhibit the activity of proangiogenic signals ( 57 ).…”