Effects of fatty acid synthase inhibitors on lymphatic vessels: An in vitro and in vivo study in a melanoma model

Article; Bagg albino mouse; C57BL mouse; Melanoma, Experimental; RNA interference; Western blotting; Animals; Apoptosis; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cerulenin; Fatty Acid Synthases; Fatty Acid Synthesis Inhibitors; Humans; Lactones; Lymphangiogenesis; Lymphatic Metastasis; Lymphatic Vessels; Melanoma; Mice, Inbred BALB C; Mice, Inbred C57BL; Reverse Transcriptase Polymerase Chain Reaction; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D

Abstract :

[en] Fatty acid synthase (FASN) is responsible for the endogenous production of fatty acids from acetyl-CoA and malonyl-CoA. Its overexpression is associated with poor prognosis in human cancers including melanomas. Our group has previously shown that the inhibition of FASN with orlistat reduces spontaneous lymphatic metastasis in experimental B16-F10 melanomas, which is a consequence, at least in part, of the reduction of proliferation and induction of apoptosis. Here, we sought to investigate the effects of pharmacological FASN inhibition on lymphatic vessels by using cell culture and mouse models. The effects of FASN inhibitors cerulenin and orlistat on the proliferation, apoptosis, and migration of human lymphatic endothelial cells (HDLEC) were evaluated with in vitro models. The lymphatic outgrowth was evaluated by using a murine ex vivo assay. B16-F10 melanomas and surgical wounds were produced in the ears of C57Bl/6 and Balb-C mice, respectively, and their peripheral lymphatic vessels evaluated by fluorescent microlymphangiography. The secretion of vascular endothelial growth factor C and D (VEGF-C and -D) by melanoma cells was evaluated by ELISA and conditioned media used to study in vitro lymphangiogenesis. Here, we show that cerulenin and orlistat decrease the viability, proliferation, and migration of HDLEC cells. The volume of lymph node metastases from B16-F10 experimental melanomas was reduced by 39% in orlistat-treated animals as well as the expression of VEGF-C in these tissues. In addition, lymphatic vessels from orlistat-treated mice drained more efficiently the injected FITC-dextran. Orlistat and cerulenin reduced VEGF-C secretion and, increase production of VEGF-D by B16-F10 and SK-Mel-25 melanoma cells. Finally, reduced lymphatic cell extensions, were observed following the treatment with conditioned medium from cerulenin- and orlistat-treated B16-F10 cells. Altogether, our results show that FASN inhibitors have anti-metastatic effects by acting on lymphatic endothelium and melanoma cells regardless the increase of lymphatic permeability promoted by orlistat. © 2017 USCAP, Inc All rights reserved.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Bastos, Débora Campanella; Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Av. Limeira 901, CP 52, Areão, Piracicaba, SP, Brazil

Paupert, Jenny ; Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium

Maillard, Catherine ; Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium

Seguin, Fabiana; Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Av. Limeira 901, CP 52, Areão, Piracicaba, SP, Brazil

Carvalho, Marco A.; Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Av. Limeira 901, CP 52, Areão, Piracicaba, SP, Brazil

Agostini, Michelle; Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Av. Limeira 901, CP 52, Areão, Piracicaba, SP, Brazil

Coletta, Ricardo D.; Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Av. Limeira 901, CP 52, Areão, Piracicaba, SP, Brazil

Noël, Agnès ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Graner, Edgard; Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Av. Limeira 901, CP 52, Areão, Piracicaba, SP, Brazil

Language :

English

Title :

Effects of fatty acid synthase inhibitors on lymphatic vessels: An in vitro and in vivo study in a melanoma model

Publication date :

2017

Journal title :

Laboratory Investigation

ISSN :

0023-6837

eISSN :

1530-0307

Publisher :

Nature Publishing Group

Volume :

Issue :

Pages :

194-206

Peer reviewed :

Peer Reviewed verified by ORBi

Name of the research project :

FAPESP Grants 2008/57471-7; FAPESP Grants 2014/20832-3; FAPESP fellowships (2010/51090-1, 2010/50946-0, 2008/55548-2, 2007/58158-8)

Funders :

FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo
F.R.S.-FNRS - Fonds de la Recherche Scientifique
Fondation contre le Cancer

Available on ORBi :

since 09 February 2018

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