title: 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.
abstract: 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.
authors.affiliation: UMRS U938, Hôpital Saint-Antoine 75012 Paris, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Younes
authors.affiliation: UMRS U938, Hôpital Saint-Antoine 75012 Paris, France. UMRS 1007 Université Paris Descartes 45, rue des Saints-Pères 75270 Paris cedex 06.
authors.forename: Zherui
authors.initials: Z
authors.lastname: Wu
authors.affiliation: UMRS U938, Hôpital Saint-Antoine 75012 Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Dupouy
authors.affiliation: Pathology Department, Université Paris Descartes, Hôpitaux Universitaires Cochin Hôtel-Dieu Broca, 75014 Paris, France.
authors.forename: Audrey Mansuet
authors.initials: AM
authors.lastname: Lupo
authors.affiliation: UMRS U938, Hôpital Saint-Antoine 75012 Paris, France. Pathology Department Hôpital Saint-Antoine 75012 Paris, France.
authors.forename: Najat
authors.initials: N
authors.lastname: Mourra
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Pathology Department Hôpital Saint-Antoine 75012 Paris, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Fléjou
authors.affiliation: UMRS 1007 Université Paris Descartes 45, rue des Saints-Pères 75270 Paris cedex 06. Thoracic Oncology Department Hôpital Saint-Joseph and Université Paris Descartes 75014 Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Trédaniel
authors.affiliation: Thoracic Surgery Department, Université Paris Descartes, Hôpitaux Universitaires Cochin Hôtel-Dieu Broca, 75014 Paris, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Régnard
authors.affiliation: Pathology Department, Université Paris Descartes, Hôpitaux Universitaires Cochin Hôtel-Dieu Broca, 75014 Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Damotte
authors.affiliation: UMRS 1007 Université Paris Descartes 45, rue des Saints-Pères 75270 Paris cedex 06. Thoracic Surgery Department, Université Paris Descartes, Hôpitaux Universitaires Cochin Hôtel-Dieu Broca, 75014 Paris, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Alifano
authors.affiliation: UMRS 1007 Université Paris Descartes 45, rue des Saints-Pères 75270 Paris cedex 06.
authors.forename: Patricia
authors.initials: P
authors.lastname: Forgez
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017024:Chemotherapy, Adjuvant; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008819:Mice, Nude; D008875:Middle Aged; D009367:Neoplasm Staging; D020890:Neuregulin-1 / Q000378:metabolism; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D066257:Heparin-binding EGF-like Growth Factor; D020781:Matrix Metalloproteinase 1; D020890:Neuregulin-1; D009496:Neurotensin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D018028:Receptors, Neurotensin; C587883:HBEGF protein, human; C094131:NRG1 protein, human; C114036:neurotensin type 1 receptor; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C522360:MMP1 protein, human