Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib
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Mohamad Younes1,*, Zherui Wu1,2,*, Sandra Dupouy1,*, Audrey Mansuet Lupo3, Najat Mourra1,4, Takashi Takahashi5, Jean François Fléjou4, Jean Trédaniel2,6, Jean François Régnard7, Diane Damotte3, Marco Alifano2,7, Patricia Forgez2
1 UMRS U938, Hôpital Saint-Antoine 75012 Paris, France.
2 UMRS 1007 Université Paris Descartes 45, rue des Saints-Pères 75270 Paris cedex 06.
3 Pathology Department, Université Paris Descartes, Hôpitaux Universitaires Cochin Hôtel-Dieu Broca, 75014 Paris, France.
4 Pathology Department Hôpital Saint-Antoine 75012 Paris, France.
5 Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya 466-8550, Japan.
6 Thoracic Oncology Department Hôpital Saint-Joseph and Université Paris Descartes 75014 Paris, France.
7 Thoracic Surgery Department, Université Paris Descartes, Hôpitaux Universitaires Cochin Hôtel-Dieu Broca, 75014 Paris, France.
* MY, ZW, and SD contributed equally to this work.
Patricia Forgez, e-mail: Patricia.firstname.lastname@example.org
Key words: Cancer growth and metastasis, neurotensin, EGFR, HER2, HER3, EGF like ligands.
Received: November 28, 2013 Accepted: May 07, 2014, Published: September 26, 2014
Alterations in the signaling pathways of epidermal growth factor receptors (HERs) are associated with tumor aggressiveness. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 60% of lung cancers. In a previous clinical study, NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in a selected population of stage I lung adenocarcinomas treated by surgery alone. In a second study, shown here, the frequent and high expression of NTSR1 was correlated with a pejorative prognosis in 389 patients with stage I to III lung adenocarcinoma, and was an independent prognosis marker.
Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here we highlight the cellular mechanisms activated by Neurotensin (NTS) and its high affinity receptor (NTSR1) contributing to lung cancer cell aggressiveness. We show that the NTS autocrine and/or paracrine regulation causes EGFR, HER2, and HER3 over-expression and activation in lung tumor cells. The EGFR and HER3 autocrine activation is mediated by MMP1 activation and EGF “like” ligands (HB-EGF, Neuregulin 1) release. By establishing autocrine and/or paracrine NTS regulation, we show that tumor growth is modulated according to NTS expression, with a low growth rate in those tumors that do not express NTS. Accordingly, xenografted tumors expressing NTS and NTSR1 showed a positive response to erlotinib, whereas tumors void of NTSR1 expression had no detectable response. This is consistent with the presence of a NTS autocrine loop, leading to the sustained activation of EGFR and responsible for cancer aggressiveness.
We propose the use of NTS/NTSR1 tumor expression, as a biomarker for the use of EGFR tyrosine kinase inhibitors in patients lacking EGFR mutation.
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