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Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

Vasohibin‐2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL‐Kras (G12D) ; LSL‐Trp53 (...

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Autores principales: Iida‐Norita, Rie, Kawamura, Minaho, Suzuki, Yasuhiro, Hamada, Shin, Masamune, Atsushi, Furukawa, Toru, Sato, Yasufumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609860/
https://www.ncbi.nlm.nih.gov/pubmed/31074083
http://dx.doi.org/10.1111/cas.14041
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author Iida‐Norita, Rie
Kawamura, Minaho
Suzuki, Yasuhiro
Hamada, Shin
Masamune, Atsushi
Furukawa, Toru
Sato, Yasufumi
author_facet Iida‐Norita, Rie
Kawamura, Minaho
Suzuki, Yasuhiro
Hamada, Shin
Masamune, Atsushi
Furukawa, Toru
Sato, Yasufumi
author_sort Iida‐Norita, Rie
collection PubMed
description Vasohibin‐2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL‐Kras (G12D) ; LSL‐Trp53 (R172H) ; Pdx‐1‐Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2‐knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2‐deficient mice, metastasis was significantly decreased in Vash2‐deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2‐induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2‐deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.
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spelling pubmed-66098602019-07-15 Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma Iida‐Norita, Rie Kawamura, Minaho Suzuki, Yasuhiro Hamada, Shin Masamune, Atsushi Furukawa, Toru Sato, Yasufumi Cancer Sci Original Articles Vasohibin‐2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL‐Kras (G12D) ; LSL‐Trp53 (R172H) ; Pdx‐1‐Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2‐knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2‐deficient mice, metastasis was significantly decreased in Vash2‐deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2‐induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2‐deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity. John Wiley and Sons Inc. 2019-06-18 2019-07 /pmc/articles/PMC6609860/ /pubmed/31074083 http://dx.doi.org/10.1111/cas.14041 Text en © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Iida‐Norita, Rie
Kawamura, Minaho
Suzuki, Yasuhiro
Hamada, Shin
Masamune, Atsushi
Furukawa, Toru
Sato, Yasufumi
Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma
title Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma
title_full Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma
title_fullStr Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma
title_full_unstemmed Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma
title_short Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma
title_sort vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609860/
https://www.ncbi.nlm.nih.gov/pubmed/31074083
http://dx.doi.org/10.1111/cas.14041
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