Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor, Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs. © 2012.

Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor / A. D., Florio; Veronica, Sancho; Paola, Moreno; DELLE FAVE, Gianfranco; Robert T., Jensen. - In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH. - ISSN 0167-4889. - STAMPA. - 1833:3(2013), pp. 573-582. [10.1016/j.bbamcr.2012.11.021]

Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor

DELLE FAVE, Gianfranco;
2013

Abstract

Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor, Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs. © 2012.
2013
adenoma; animals; blotting; cell growth; cell proliferation; cultured; drug effects; drug therapy/metabolism/pathology; epidermal growth factor; gastrointestinal hormones; humans; islet cell; metabolism; neuroendocrine tumors; pancreatic endocrine tumors; pancreatic neoplasms; pharmacology; phosphorylation; rats; reactive oxygen species; receptor; signal transduction; somatostatinoma; transactivation; transcriptional activation; transforming growth factor alpha; tumor cells; tyrosine; western
01 Pubblicazione su rivista::01a Articolo in rivista
Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor / A. D., Florio; Veronica, Sancho; Paola, Moreno; DELLE FAVE, Gianfranco; Robert T., Jensen. - In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH. - ISSN 0167-4889. - STAMPA. - 1833:3(2013), pp. 573-582. [10.1016/j.bbamcr.2012.11.021]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/514834
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