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Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling
BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be resp...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880584/ https://www.ncbi.nlm.nih.gov/pubmed/29151594 http://dx.doi.org/10.1038/ijo.2017.285 |
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author | Carbone, C Piro, G Gaianigo, N Ligorio, F Santoro, R Merz, V Simionato, F Zecchetto, C Falco, G Conti, G Kamga, P T Krampera, M Di Nicolantonio, F De Franceschi, L Scarpa, A Tortora, G Melisi, D |
author_facet | Carbone, C Piro, G Gaianigo, N Ligorio, F Santoro, R Merz, V Simionato, F Zecchetto, C Falco, G Conti, G Kamga, P T Krampera, M Di Nicolantonio, F De Franceschi, L Scarpa, A Tortora, G Melisi, D |
author_sort | Carbone, C |
collection | PubMed |
description | BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS), RESULTS: We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPO(CM)) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSC(CM)) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPO(CM) induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer. |
format | Online Article Text |
id | pubmed-5880584 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-58805842018-04-04 Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling Carbone, C Piro, G Gaianigo, N Ligorio, F Santoro, R Merz, V Simionato, F Zecchetto, C Falco, G Conti, G Kamga, P T Krampera, M Di Nicolantonio, F De Franceschi, L Scarpa, A Tortora, G Melisi, D Int J Obes (Lond) Original Article BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS), RESULTS: We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPO(CM)) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSC(CM)) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPO(CM) induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer. Nature Publishing Group 2018-03 2018-01-16 /pmc/articles/PMC5880584/ /pubmed/29151594 http://dx.doi.org/10.1038/ijo.2017.285 Text en Copyright © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Carbone, C Piro, G Gaianigo, N Ligorio, F Santoro, R Merz, V Simionato, F Zecchetto, C Falco, G Conti, G Kamga, P T Krampera, M Di Nicolantonio, F De Franceschi, L Scarpa, A Tortora, G Melisi, D Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling |
title | Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling |
title_full | Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling |
title_fullStr | Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling |
title_full_unstemmed | Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling |
title_short | Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling |
title_sort | adipocytes sustain pancreatic cancer progression through a non-canonical wnt paracrine network inducing ror2 nuclear shuttling |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880584/ https://www.ncbi.nlm.nih.gov/pubmed/29151594 http://dx.doi.org/10.1038/ijo.2017.285 |
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