The 5-HT(2B) receptor plays a key regulatory role in both neuroendocrine tumor cell proliferation and the modulation of the fibroblast component of the neoplastic microenvironment

Cancer. 2010 Jun 15;116(12):2902-12. doi: 10.1002/cncr.25049.


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-HT(2B) receptors on tumor cells would inhibit SI-NET 5-HT release and, thereby, fibroblast activation in the tumor microenvironment.

Methods: We studied the 5-HT(2B) 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-HT(2B) expressing SI-NET cell line, KRJ-I, PRX-08066 inhibited proliferation (IC(50) 4.6 x 10(-9)M) and 5-HT secretion (6.9 x 10(-9)M) and decreased ERK1/2 phosphorylation and profibrotic growth factor synthesis and secretion (transforming growth factor beta 1 [TGFbeta1], 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%), TGFbeta1, CTGF, and FGF2 transcription (20%-50%) in the KRJ-I cell line. 5-HT itself stimulated HEK293 proliferation (25%) and synthesis of TGFbeta1, CTGF and FGF2. PRX-08066 inhibition of KRJ-I function reversed these effects in the coculture system.

Conclusions: Targeting the 5-HT(2B) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Coculture Techniques
  • Fibroblasts / drug effects*
  • Fibroblasts / pathology
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Ki-67 Antigen / metabolism
  • Neuroendocrine Tumors / metabolism*
  • Neuroendocrine Tumors / pathology*
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin / metabolism
  • Serotonin 5-HT2 Receptor Antagonists
  • Signal Transduction / drug effects


  • Intercellular Signaling Peptides and Proteins
  • Ki-67 Antigen
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin
  • Caspase 3