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Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity

Cancer-associated fibroblasts (CAFs) play a crucial role in cancer progression, drug resistance and tumor recurrence. We have recently shown that the Notch pathway determines the tumor-regulatory role of experimentally created ‘CAFs’. Here, we examined the status of Notch signaling in human melanoma...

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Autores principales: Shao, Hongwei, Moller, Mecker, Cai, Long, Prokupets, Rochelle, Yang, Cuixia, Costa, Connor, Yu, Kerstin, Le, Nga, Liu, Zhao-Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951899/
https://www.ncbi.nlm.nih.gov/pubmed/33705467
http://dx.doi.org/10.1371/journal.pone.0248260
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author Shao, Hongwei
Moller, Mecker
Cai, Long
Prokupets, Rochelle
Yang, Cuixia
Costa, Connor
Yu, Kerstin
Le, Nga
Liu, Zhao-Jun
author_facet Shao, Hongwei
Moller, Mecker
Cai, Long
Prokupets, Rochelle
Yang, Cuixia
Costa, Connor
Yu, Kerstin
Le, Nga
Liu, Zhao-Jun
author_sort Shao, Hongwei
collection PubMed
description Cancer-associated fibroblasts (CAFs) play a crucial role in cancer progression, drug resistance and tumor recurrence. We have recently shown that the Notch pathway determines the tumor-regulatory role of experimentally created ‘CAFs’. Here, we examined the status of Notch signaling in human melanoma-associated fibroblasts (MAFs) versus their normal counterparts and tested whether manipulation of the Notch pathway activity in MAFs alters their tumor-regulatory function. Using tissue microarrays, we found that MAFs exhibit decreased Notch pathway activity compared with normal fibroblasts in adjacent and non-adjacent skin. Consistently, MAFs isolated from human metastatic melanoma exhibited lower Notch activity than did normal human fibroblasts, demonstrating that Notch pathway activity is low in MAFs. We then investigated the effect of increasing Notch pathway activity in MAF on melanoma growth in co-cultures and in a mouse co-graft model. We found that activation of the Notch pathway in MAFs significantly restricted melanoma cell growth in vitro and suppressed melanoma skin growth and tumor angiogenesis in vivo. Our study demonstrates that the Notch signaling is inhibited in MAFs. Increase of Notch pathway activity can confer tumor-suppressive function on MAFs. Thus, targeting melanoma by activating Notch signaling in MAF may represent a novel therapeutic approach.
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spelling pubmed-79518992021-03-22 Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity Shao, Hongwei Moller, Mecker Cai, Long Prokupets, Rochelle Yang, Cuixia Costa, Connor Yu, Kerstin Le, Nga Liu, Zhao-Jun PLoS One Research Article Cancer-associated fibroblasts (CAFs) play a crucial role in cancer progression, drug resistance and tumor recurrence. We have recently shown that the Notch pathway determines the tumor-regulatory role of experimentally created ‘CAFs’. Here, we examined the status of Notch signaling in human melanoma-associated fibroblasts (MAFs) versus their normal counterparts and tested whether manipulation of the Notch pathway activity in MAFs alters their tumor-regulatory function. Using tissue microarrays, we found that MAFs exhibit decreased Notch pathway activity compared with normal fibroblasts in adjacent and non-adjacent skin. Consistently, MAFs isolated from human metastatic melanoma exhibited lower Notch activity than did normal human fibroblasts, demonstrating that Notch pathway activity is low in MAFs. We then investigated the effect of increasing Notch pathway activity in MAF on melanoma growth in co-cultures and in a mouse co-graft model. We found that activation of the Notch pathway in MAFs significantly restricted melanoma cell growth in vitro and suppressed melanoma skin growth and tumor angiogenesis in vivo. Our study demonstrates that the Notch signaling is inhibited in MAFs. Increase of Notch pathway activity can confer tumor-suppressive function on MAFs. Thus, targeting melanoma by activating Notch signaling in MAF may represent a novel therapeutic approach. Public Library of Science 2021-03-11 /pmc/articles/PMC7951899/ /pubmed/33705467 http://dx.doi.org/10.1371/journal.pone.0248260 Text en © 2021 Shao et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Shao, Hongwei
Moller, Mecker
Cai, Long
Prokupets, Rochelle
Yang, Cuixia
Costa, Connor
Yu, Kerstin
Le, Nga
Liu, Zhao-Jun
Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity
title Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity
title_full Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity
title_fullStr Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity
title_full_unstemmed Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity
title_short Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity
title_sort converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular notch1 pathway activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951899/
https://www.ncbi.nlm.nih.gov/pubmed/33705467
http://dx.doi.org/10.1371/journal.pone.0248260
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