Angiogenesis in Neuroendocrine Tumors: Therapeutic Applications

Abstract

The considerable research efforts devoted to the understanding of the mechanisms of tumor angiogenesis have resulted in the development of targeted anti-angiogenic therapies and finally in their introduction in clinical practice. Neuroendocrine tumors (NETs), which are characterized by a high vascular supply and a strong expression of VEGF-A, one of the most potent pro-angiogenic factors, are an attractive indication for these new treatments. However, several lines of evidence show that the dense vascular networks associated with low-grade NETs are more likely to be a marker of differentiation than a marker of aggressiveness, as in other epithelial tumors. These observations form the basis for the so-called ‘neuroendocrine paradox’, according to which the most vascularized are the most differentiated and the less angiogenic NETs. This must be kept in mind when discussing the role of anti-angiogenic strategies in the treatment of NETs. Nevertheless, several targeted therapies, with direct or indirect anti-angiogenic properties, including anti-VEGF antibodies, tyrosine kinase inhibitors (sunitinib) and mTOR inhibitors (everolimus), have recently proven to be of clinical benefit. In addition, some drugs already used in NET treatment, such as somatostatin analogues and interferon-α, may also have anti-angiogenic properties. The main challenges for the next future are to validate biomarkers for the selection of patients and the prediction of their response to refine the indications of anti-angiogenic targeted therapies and to overcome the mechanisms of resistance, which explain the limited duration of action of most of these treatments.

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

“…Low-grade NETs have extraordinary vascularisation, but it is diminished in more aggressive tumours (Marion-Audibert et al 2003). In islet cell tumours, higher microvascular density (MVD) and VEGF (VEGFA) expression predict a more favourable prognosis (Couvelard et al 2005) and this has been called the 'neuroendocrine paradox' (Scoazec 2013).…”

Zebrafish as an innovative model for neuroendocrine tumors

“…In these tumors intratumoral microvascular density is higher in benign lesions than in carcinomas. Surprisingly, in malignant tumors microvascular density seems to be a favorable parameter, associated with a prolonged survival (Scoazec 2013). In addition, direct or indirect signs of proangiogenic response and hypoxia are expressed more clearly in high-grade than in low-grade tumors.…”

“…Most NETs have a highly diffuse vascularization. In fact, NETs typically produce a variety of proangiogenic cytokines and growth factors, including several members of VEGF, FGF, PDGF, epidermal growth factor (EGF), and insulin-like growth factor (IGF) families (Teule & Casanovas 2012, Scoazec 2013.…”

“…To explain these observations, it has been postulated that in pancreatic NETs: i) the density of the vascular network is a marker of differentiation rather than a marker of aggressiveness; ii) angiogenesis is not tightly connected to metastatic properties. Therefore the most vascularized pancreatic NETs appear to be the most differentiated and the less angiogenic neoplasms (Scoazec 2013). In this regard, several issues need to be still addressed.…”

Neuroendocrine tumors of the digestive system: pathologic and molecular characteristics

“…В отдельных работах предпринимаются попытки из-учить роль определения в опухоли экспрессии таких маркеров, как 6-метилгуанин-ДНК-метилтрансфера-за (MGMT), р53, фактор роста эндотелия сосудов (VEGF) и его рецепторы VEGFR1-3, инсулиноподоб-ный фактор роста (IGF), рецепторы тирозинкиназы (с-Кit, EGFR) и ряд других белков [63][64][65][66][67]. Прово-дятся также молекулярно-генетические исследования, направленные на поиск амплификаций, транслока-ций, делеций, изменений экспрессии и мутаций соот-ветствующих генов в клетках НЭО ЖКТ и ПЖ, которые, однако, пока не открыли возможностей использова-ния генетических маркеров в диагностике спорадиче-ских случаев развития данных новообразований.…”