Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum

Abstract

Small intestinal neuroendocrine tumours (SI-NETs) are neoplasms characterized by their ability to secrete biogenic amines and peptides. These cause distinct clinical pathology including carcinoid syndrome, marked by diarrhoea and flushing, as well as fibrosis, notably mesenteric fibrosis. Mesenteric fibrosis often results in significant morbidity by causing intestinal obstruction, oedema and ischaemia. Although advancements have been made to alleviate symptoms of carcinoid syndrome and prolong the survival of patients with SI-NETs, therapeutic options for patients with mesenteric fibrosis are still limited. As improved insight in the complex pathogenesis of mesenteric fibrosis is key to the development of new therapies, we evaluated the literature for known and putative mediators of fibrosis in SI-NETs. In this review, we discuss the tumour microenvironment, growth factors and signalling pathways involved in the complex process of fibrosis development and tumour progression in SI-NETs, in order to elucidate potential new avenues for scientific research and therapies to improve the management of patients suffering from the complications of mesenteric fibrosis.

Prognostic impact of a large mesenteric mass >2 cm in ileal neuroendocrine tumors

“…i‐NETs secrete serotonin and other factors, and thereby interact with the tumor microenvironment, including cancer‐associated fibroblasts, causing a mesenteric desmoplastic reaction and LMM . Therefore, the presence of mesenteric desmoplasia/mass may represent aggressive biology; though the prognostic impact is not clear .…”

Update on Pathophysiology, Treatment, and Complications of Carcinoid Syndrome

“…Fibrotic complications of secreting NEN such as carcinoid heart disease and mesenteric fibrosis are the result of increased fibrosis formation within the cardiac valves and mesentery [15,45]. One of the main factors driving fibrosis formation is thought to be serotonin since these complications occur mainly in patients with raised urine 5-HIAA, a breakdown product of serotonin [45][46][47]. Figure 1 summarizes the components and growth factors in the development of fibrosis formation.…”

“…Fibroblasts are stimulated by serotonin but also directly and indirectly by several growth factors, transforming growth factor beta (TGF-B), platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF2), and connective tissue growth factor (CTGF or CCN2). TGF-B stimulates PDGF which has a strong proliferative effect on fibroblasts and FGF2 which has a strong mitogenic effect on fibroblasts [47]. e connective tissue growth factor is induced by serotonin and TGF-B and increases collagen synthesis, fibroblast proliferation, and differentiation into myofibroblasts [47][48][49].…”

“…TGF-B stimulates PDGF which has a strong proliferative effect on fibroblasts and FGF2 which has a strong mitogenic effect on fibroblasts [47]. e connective tissue growth factor is induced by serotonin and TGF-B and increases collagen synthesis, fibroblast proliferation, and differentiation into myofibroblasts [47][48][49]. Multiple immune cells including B-and T cells, NK cells, dendritic cells, mast cells, and tumour-associated macrophages (TAM) infiltrate the NEN tumour microenvironment creating an immunosuppressed environment, suppression of the immune response, and stimulation of fibroblast proliferation and myofibroblastic differentiation resulting in fibrosis formation.…”

“…Multiple immune cells including B-and T cells, NK cells, dendritic cells, mast cells, and tumour-associated macrophages (TAM) infiltrate the NEN tumour microenvironment creating an immunosuppressed environment, suppression of the immune response, and stimulation of fibroblast proliferation and myofibroblastic differentiation resulting in fibrosis formation. e transforming growth factor beta stimulates the third main component of TME, the extracellular matrix stimulating extracellular matrix remodelling and production which contributes to fibrosis formation [47,49,50].…”