Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

Abstract

Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10-40% of patients with well-differentiated neuroendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field.

Keywords: carcinoid syndrome; neuroendocrine tumors; pharmacological treatment; preclinical models; serotonin; xenograft.

Figure 1

The main pathways involved in carcinoid syndrome and related drugs. (a) The main pathway involved in carcinoid syndrome (CS) is related to serotonin (5-HT). Drugs able to block this pathway act through inhibition of tryptophan hydroxylase 1 (TPH1), the isoform expressed in enterochromaffin cells of the gastrointestinal tract (EC cell), or modulation of 5-HT receptors (5-HTRs). TPH1 inhibitors currently studied are telotristat ethyl (TE) and mol002291. Other drugs acting through interaction with 5-HT receptors (5-HTRs) are alosetron and ondansetron (both 5-HT3 receptor antagonists), terguride (5-HT_2B/2C receptor antagonist) and CSTI-300 (5-HT3 receptor partial agonist). (b) Regarding fibrotic complications of the CS, transforming growth factor beta (TGF-β) can be produced by cancer cells and acts on the fibroblasts by stimulating the production of TGF-β itself. The components of tumor microenvironment induce the expression of platelet-derived growth factor receptor β (PDGFRβ) on fibroblasts and upregulate their activity in a paracrine manner. Tamoxifen and imatinib are able to affect TGF-β and PDGF secretion with potential application in the therapy of CS. (c) Considering oncogenic cellular signaling pathways, the pan-PI3K inhibitor, BKM120, and the dual PI3K/mTOR inhibitor, BEZ235, decrease proliferation in multiple NET cell lines. Inhibition of PTEN with concomitant increased Akt signaling decreases secretion of 5-HT due to reduced expression of TPH1. Everolimus targets mTOR complex 1 (mTORC1), but its effect is not durable in patients with NETs because of the unsustained inhibition of mTORC1 signaling and/or activation of mTORC2, that is targeted by CC-223, a second generation mTORC1/2 inhibitor.

Figure 2

Tumorigenic potential of BON-1 cells implanted in zebrafish embryos. Red-stained BON-1 cells were implanted in 48 hpf Tg(fli1a:EGFP)^y1 zebrafish embryos. Epifluorescence images at 24 hpi of PBS-injected embryos (control; (a)) and BON-1 (red) xenografted embryos (b,c). The red channel was omitted in panel b to facilitate the observation of tumor-induced angiogenesis (green). BON-1 xenograft induced the formation of endothelial structures (green) sprouting from the subintestinal vein plexus within 24 h. Overlay of representative fluorescent and bright field images of grafted embryos at 0 (d) and 48 hpi (e,f) showed the spread of tumor cells throughout the embryo body (black arrowhead). The tail particular at 48 hpi was imaged (f). Embryos are shown anterior to the left. Scale bar, 100 µm.