25 3 Endocrine-Related A Blaževic´ et al. Fibrosis and small intestinal 25:3 R115–R130 Cancer neuroendocrine tumours REVIEW Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum Anela Blažević, Johannes Hofland, Leo J Hofland, Richard A Feelders and Wouter W de Herder Department of Internal Medicine, Sector Endocrinology, ENETS Centre of Excellence, Erasmus University Medical Center (Erasmus MC) and Erasmus MC Cancer Institute, Rotterdam, Netherlands Correspondence should be addressed to A Blaževic´: [email protected] Abstract Small intestinal neuroendocrine tumours (SI-NETs) are neoplasms characterized by their Key Words ability to secrete biogenic amines and peptides. These cause distinct clinical pathology f neuroendocrine tumour including carcinoid syndrome, marked by diarrhoea and flushing, as well as fibrosis, f fibrosis notably mesenteric fibrosis. Mesenteric fibrosis often results in significant morbidity by f growth factors causing intestinal obstruction, oedema and ischaemia. Although advancements have f targeted therapy been made to alleviate symptoms of carcinoid syndrome and prolong the survival of f tumour microenvironment 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 Endocrine-Related Cancer suffering from the complications of mesenteric fibrosis. (2018) 25, R115–R130 Introduction Small intestinal neuroendocrine tumours (SI-NETs) are rare Another hallmark of SI-NETs is the ability to induce and mostly slow-growing neoplasms originating from the fibrosis. The fibrosis can occur around the tumour or at enterochromaffin (EC) cells of the intestine de( Herder 2005, distant sites (Modlin et al. 2004, Niederle et al. 2016). Yao et al. 2008). EC cells are chemo- and mechanosensory cells Endocardial fibrosis of the right heart valves, known as that integrate signals from the bowel content and peristalsis carcinoid heart disease, is the most frequent distant fibrotic and communicate with the neural sensory system in order complication that occurs in 20–30% of SI-NET patients. to control gut motility, secretion and visceral sensation Carcinoid heart disease is associated with metastatic (Linan-Rico et al. 2016, Bellono et al. 2017). Retention of the disease and carcinoid syndrome, suggesting an etiological ability of EC cells to secrete amines and peptides can cause role for circulating tumour-secreted factors (Modlin et al. distinct hormonal syndromes in SI-NETs (de Herder 2005, 2004, de Herder 2005, Niederle et al. 2016). However, in Yao et al. 2008). Carcinoid syndrome, marked by diarrhoea this review, we will focus on local fibrotic complications, of and flushing, is the most established of these hormonal which mesenteric fibrosis (MF) is most notable and occurs syndromes and is caused by release of 5-hydroxytryptamine in up to 50% of SI-NET patients (Rodriguez Laval et al. (serotonin), tachykinins and bradykinins and many other 2017). It is caused by a metastatic lesion circumscribed mediators (de Herder 2005, Halperin et al. 2017). by an extensive fibrotic reaction in the mesentery http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0380 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 11:36:45AM via free access 10.1530/ERC-17-0380 Endocrine-Related A Blaževic´ et al. Fibrosis and small intestinal 25:3 R116 Cancer neuroendocrine tumours neuroendocrine tumours. The search strategy is provided in the Supplementary Data (see section on supplementary data given at the end of this article). The reference lists of included studies and relevant reviews were assessed to identify additional articles. Results Tumour microenvironment (TME) Tissue homeostasis is maintained by intricate interactions between cells and their microenvironment. Bidirectional communication between SI-NET cells and other components of the TME alters the composition of the microenvironment that can become profibrotic and tumourigenic. Therefore, understanding the TME is crucial in order to decipher how SI-NETs induce fibrosis (Quail & Joyce 2013). Over the last decades, cancer research has been increasingly focused on the TME and found many commonalities with chronic wound healing that results in fibrosis Rybinski( et al. 2014). The local microenvironment of cancer cells is commonly referred to as ‘reactive stroma’. This reactive tumour stroma consists of immune cells, fibroblasts, capillaries, basement membrane and extracellular matrix (ECM). The TME is Figure 1 Coronal CT-image showing typical mesenteric fibrosis as radiating strands crucial for tumour growth, invasion and metastasis, with of soft-tissue (arrow) surrounding a metastatic mesenteric mass. both cancer-promoting as cancer-restraining actions of most components and is known to differ between (Fig. 1). MF leads in a significant percentage of patients cancer types (Quail & Joyce 2013). The tumour stroma to intestinal obstruction, oedema and ischaemia, which of SI-NETs differs from other cancers with a characteristic causes abdominal pain, cachexia and often necessitates desmoplastic reaction and limited leukocytic infiltration surgery (Makridis et al. 1990, Öhrvall et al. 2000, Druce (Chaudhry et al. 1992, Pantongrag-Brown et al. 1995, et al. 2010). To date, surgery is the only treatment option Zhang et al. 2004). Therefore, the pathobiological for patients with complaints due to MF (Makridis et al. processes in the SI-NET TME differ from other cancer 1990, Modlin et al. 2004). Because survival of patients types. Moreover, because of the commonalities between improved since the development of targeted and more pathways involved in development of fibrosis and cancer effective therapies for carcinoid syndrome and tumour progression, insight gained in the distinct effects of growth control, there is increased need for advancements different TME components in SI-NETs can result both in in treatment options for MF (Niederle et al. 2016, Pavel effective anticancer as well as antifibrotic treatment. et al. 2016). As improved knowledge of the pathogenesis Fibroblasts are the dominant cellular component of fibrosis is key to the development of new therapies, we of tumour stroma, next to tumour cells. The majority assessed in this review literature on putative mediators of of these fibroblasts have a modified phenotype, similar MF in SI-NETs and treatments targeting these factors. to fibroblasts during wound healing. This activated phenotype of cancer-associated fibroblasts (CAFs) is identified by expression of α-smooth muscle actin Methods (αSMA). In contrast to quiescent fibroblasts, CAFs are MEDLINE, EMBASE, Web of Science, Cochrane CENTRAL able to proliferate, produce growth factors and ECM and Google Scholar (first 100 results) were systematically (Kalluri 2016). Compared to other neuroendocrine searched in February 2017. The search strategy was tumours, SI-NETs have a high expression of αSMA in designed to search highly sensitive for studies on fibrosis in the fibroblast component of the TME both in primary http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0380 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 11:36:45AM via free access Endocrine-Related A Blaževic´ et al. Fibrosis and small intestinal 25:3 R117 Cancer neuroendocrine tumours tumours and metastases (Facco et al. 1998, Kidd et al. (Kidd et al. 2007c). Next to collagen, the ECM can contain 2007c, Cunningham et al. 2010). Further evidence on the various proteoglycans such as heparan and chondroitin presence of synthetic fibroblasts in SI-NETs was detected sulfate (Cox & Erler 2011). Analysis of transcription in primary cultures in which cells from the tumour levels of these proteoglycans in NETs showed changes stroma developed the typical stellate shape of CAFs and during disease progression; however, their role in tumour increased growth factor transcription after stimulation progression and development of fibrosis in SI-NETs is still with transforming growth factor beta 1 (TGFβ1, see later) elusive (García-Suárez et al. 2014). (Kidd et al. 2007c). This suggests that also in SI-NETs, CAFs are important regulators of fibrotic stromal programmes. Profibrotic growth factors Immune cells are another important constituent As mentioned earlier, deregulation of signals changes the of the TME, and dysregulation of the local immune microenvironment resulting in tumour progression and system and inflammatory response is implicated in both fibrosis. Therefore, along with understanding the TME, it tumourigenesis and development of fibrosis (Wynn is important to investigate the signalling molecules that 2008, Rybinski et al. 2014). A major component of the mediate these changes. These molecules, which regulate leukocytic infiltrate in the TME is the tumour-associated cell-fate processes such as proliferation, differentiation macrophages (TAMs)