The 5‐HT2B receptor plays a key regulatory role in both neuroendocrine tumor cell proliferation and the modulation of the fibroblast component of the neoplastic microenvironment

BACKGROUND: Fibrosis is a cardinal feature of small intestinal neuroendocrine tumors (SI‐NETs) both in local peritumoral tissue and systemic sites (cardiac). 5‐HT, a commonly secreted NET amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibro...

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Published in:Cancer 2010-06, Vol.116 (12), p.2902-2912
Main Authors: Svejda, Bernhard, Kidd, Mark, Giovinazzo, Francesco, Eltawil, Karim, Gustafsson, Bjorn I, Pfragner, Roswitha, Modlin, Irvin M.
Format: Article
Language:English
Subjects:
Biological and medical sciences
carcinoid
coculture
fibrosis
gastrointestinal
HEK293
KRJ‐I
Medical sciences
neuroendocrine tumor
proliferation
serotonin
tumor microenvironment
Tumors
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Summary:BACKGROUND: Fibrosis is a cardinal feature of small intestinal neuroendocrine tumors (SI‐NETs) both in local peritumoral tissue and systemic sites (cardiac). 5‐HT, a commonly secreted NET amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the tumor microenvironment are unclear. We hypothesized that targeting 5‐HT2B receptors on tumor cells would inhibit SI‐NET 5‐HT release and, thereby, fibroblast activation in the tumor microenvironment. METHODS: We studied the 5‐HT2B receptor antagonist PRX‐08066 in NET cell lines (KRJ‐I, H720) and in the coculture system (KRJ‐I cells: fibroblastic HEK293 cells) using real time polymerase chain reaction, ELISA, Ki67 immunostaining, and flow cytometry‐based caspase 3 assays to assess antiproliferative and profibrotic signaling pathways. RESULTS: In the 5‐HT2B expressing SI‐NET cell line, KRJ‐I, PRX‐08066 inhibited proliferation (IC50 4.6x10−9M) and 5‐HT secretion (6.9 × 10−9M) and decreased ERK1/2 phosphorylation and profibrotic growth factor synthesis and secretion (transforming growth factor beta 1 [TGFβ1], connective tissue growth factor [CTGF] and fibroblast growth factor [FGF2]). In the KRJ‐I:HEK293 coculture system, PRX‐08066 significantly decreased 5‐HT release (>60%), Ki67 (transcript and immunostaining: 20%‐80%), TGFβ1, CTGF, and FGF2 transcription (20%‐50%) in the KRJ‐I cell line. 5‐HT itself stimulated HEK293 proliferation (25%) and synthesis of TGFβ1, CTGF and FGF2. PRX‐08066 inhibition of KRJ‐I function reversed these effects in the coculture system. CONCLUSIONS: Targeting the 5‐HT2B receptor may be an effective antiproliferative and antifibrotic strategy for SI‐NETs because it inhibits tumor microenvironment fibroblasts as well as NET cells. Fibrosis and proliferation appear to be biologically interfaced neuroendocrine neoplasia domains. Cancer 2010. © 2010 American Cancer Society. To elucidate the inter‐relation of 5‐HT to neuroendocrine tumor microenvironment, growth regulation, and fibrosis, we developed a neuroendocrine tumor (NET) fibroblast coculture system and evaluated the antiproliferative, antifibrotic, and signaling mechanisms of a novel specific 5‐HT2B receptor antagonist. Our results demonstrate that targeting the 5‐HT2B receptor may be an effective antiproliferative and antifibrotic strategy for small intestinal NETs because it inhibits tumor microenvironment fibroblasts as well as NET cell proliferation and p
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.25049