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Autocrine growth inhibition by transforming growth factor beta-1 (TGFbeta-1) in human neuroendocrine tumour cells

A Wimmel1, B Wiedenmann, S Rosewicz

  • 1Medizinische Klinik mit Schwerpunkt Hepatologie, Gastroenterologie, Endokrinologie und Stoffwechsel, CVK, Charité, Augustenburger Platz 1, D-13353, Berlin, Germany.

Gut
|August 13, 2003
PubMed
Abstract

Insights

Transforming growth factor beta-1 (TGFbeta-1) inhibits gastroenteropancreatic neuroendocrine tumour (GEP NET) growth. This TGFbeta-1 signaling creates an autocrine loop, explaining the low proliferation rate in these GEP NETs.

Area of Science:

  • Molecular biology
  • Oncology
  • Cell signaling

Background:

  • The role of transforming growth factor beta-1 (TGFbeta-1) in neuroendocrine tumour (NET) biology was previously unknown.
  • Neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) tract are a significant area of oncological research.

Purpose of the Study:

  • To investigate the expression and biological significance of TGFbeta signaling components in GEP NETs.
  • To determine the impact of TGFbeta-1 on NET cell proliferation and identify potential therapeutic targets.

Main Methods:

  • Immunohistochemistry, RT-PCR, immunoblotting, and ELISA were used to examine TGFbeta-1 and its receptors, Smads, and related proteins in NET specimens and cell lines.
  • Transactivation assays, cell counting, soft agar assays, and flow cytometry were employed to assess TGFbeta-1's effect on gene expression and cell growth.
  • TGFbeta-1's endogenous role was evaluated using neutralizing antibodies and dominant-negative receptor constructs.

Main Results:

  • TGFbeta-1 and its receptors (TGFbetaR I, TGFbetaR II) were coexpressed in 67% of human NETs and all tested NET cell lines.
  • TGFbeta-1 treatment inhibited anchorage-dependent and -independent growth in responsive NET cell lines by inducing G1 cell cycle arrest.
  • Functional inactivation of endogenous TGFbeta revealed an autocrine antiproliferative loop in NET cells.

Conclusions:

  • GEP NET cells are subject to both paracrine and autocrine growth inhibition by TGFbeta-1.
  • TGFbeta-1 mediated growth inhibition contributes to the characteristically low proliferative index observed in GEP NETs.

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