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N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions

BACKGROUND: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown lit...

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Autores principales: Feng, Haimin, Moriyama, Taiki, Ohuchida, Kenoki, Sheng, Nan, Iwamoto, Chika, Shindo, Koji, Shirahane, Kengo, Ikenaga, Naoki, Nagai, Shuntaro, Nakata, Kohei, Mizumoto, Kazuhiro, Nakamura, Masafumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050903/
https://www.ncbi.nlm.nih.gov/pubmed/33858491
http://dx.doi.org/10.1186/s13046-021-01939-1
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author Feng, Haimin
Moriyama, Taiki
Ohuchida, Kenoki
Sheng, Nan
Iwamoto, Chika
Shindo, Koji
Shirahane, Kengo
Ikenaga, Naoki
Nagai, Shuntaro
Nakata, Kohei
Mizumoto, Kazuhiro
Nakamura, Masafumi
author_facet Feng, Haimin
Moriyama, Taiki
Ohuchida, Kenoki
Sheng, Nan
Iwamoto, Chika
Shindo, Koji
Shirahane, Kengo
Ikenaga, Naoki
Nagai, Shuntaro
Nakata, Kohei
Mizumoto, Kazuhiro
Nakamura, Masafumi
author_sort Feng, Haimin
collection PubMed
description BACKGROUND: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions. METHOD: We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone’s combination therapy on subcutaneous tumor formation and splenic xenografted mouse models. RESULTS: In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone’s combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level. CONCLUSION: NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-01939-1.
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spelling pubmed-80509032021-04-19 N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions Feng, Haimin Moriyama, Taiki Ohuchida, Kenoki Sheng, Nan Iwamoto, Chika Shindo, Koji Shirahane, Kengo Ikenaga, Naoki Nagai, Shuntaro Nakata, Kohei Mizumoto, Kazuhiro Nakamura, Masafumi J Exp Clin Cancer Res Research BACKGROUND: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions. METHOD: We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone’s combination therapy on subcutaneous tumor formation and splenic xenografted mouse models. RESULTS: In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone’s combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level. CONCLUSION: NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-01939-1. BioMed Central 2021-04-15 /pmc/articles/PMC8050903/ /pubmed/33858491 http://dx.doi.org/10.1186/s13046-021-01939-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Feng, Haimin
Moriyama, Taiki
Ohuchida, Kenoki
Sheng, Nan
Iwamoto, Chika
Shindo, Koji
Shirahane, Kengo
Ikenaga, Naoki
Nagai, Shuntaro
Nakata, Kohei
Mizumoto, Kazuhiro
Nakamura, Masafumi
N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions
title N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions
title_full N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions
title_fullStr N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions
title_full_unstemmed N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions
title_short N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions
title_sort n-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050903/
https://www.ncbi.nlm.nih.gov/pubmed/33858491
http://dx.doi.org/10.1186/s13046-021-01939-1
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