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Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway

BACKGROUND: Cancer stem cells (CSCs) play crucial role in tumor progression, drug resistance and relapse in various cancers. CSC niche is comprised of various stromal cell types including Tumor-associated macrophages (TAMs). Extrinsic ques derived from these cells help in maintenance of CSC phenotyp...

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Autores principales: Radharani, N. N. V., Yadav, Amit S., Nimma, Ramakrishna, Kumar, T. V. Santosh, Bulbule, Anuradha, Chanukuppa, Venkatesh, Kumar, Dhiraj, Patnaik, Srinivas, Rapole, Srikanth, Kundu, Gopal C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932105/
https://www.ncbi.nlm.nih.gov/pubmed/35300689
http://dx.doi.org/10.1186/s12935-022-02527-9
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author Radharani, N. N. V.
Yadav, Amit S.
Nimma, Ramakrishna
Kumar, T. V. Santosh
Bulbule, Anuradha
Chanukuppa, Venkatesh
Kumar, Dhiraj
Patnaik, Srinivas
Rapole, Srikanth
Kundu, Gopal C.
author_facet Radharani, N. N. V.
Yadav, Amit S.
Nimma, Ramakrishna
Kumar, T. V. Santosh
Bulbule, Anuradha
Chanukuppa, Venkatesh
Kumar, Dhiraj
Patnaik, Srinivas
Rapole, Srikanth
Kundu, Gopal C.
author_sort Radharani, N. N. V.
collection PubMed
description BACKGROUND: Cancer stem cells (CSCs) play crucial role in tumor progression, drug resistance and relapse in various cancers. CSC niche is comprised of various stromal cell types including Tumor-associated macrophages (TAMs). Extrinsic ques derived from these cells help in maintenance of CSC phenotype. TAMs have versatile roles in tumor progression however their function in enrichment of CSC is poorly explored. METHODS: Mouse macrophages (RAW264.7) cells were activated by interaction with conditioned media (CM) of murine breast cancer cells (4T1) into TAMs and the effect of activated macrophage (TAM) derived factors was examined on enrichment of cancer stem cells (CSCs) and tumor growth using in vitro and in vivo models. RESULTS: In this study, we report that macrophages upon interaction with breast cancer cells activate tumor promoting function and exhibit differential expression of various proteins as shown by secretome analysis using proteomics studies. Based on secretome data, we found that Interleukin-6 (IL-6) is one of the up-regulated genes expressed in activated macrophages. Further, we confirm that TAMs produce high levels of IL-6 and breast cancer cell derived factors induce IL-6 production in activated macrophages via p38-MAPK pathway. Furthermore, we demonstrate that tumor activated macrophages induce enrichment of CSCs and expression of CSC specific transcription factors such as Sox-2, Oct-3/4 and Nanog in breast cancer cells. We further prove that TAM derived IL-6 plays a key role in TAM mediated CSC enrichment through activation of Signal transducer and activator of transcription 3 (STAT-3) signaling. TAM derived IL-6 influences breast cancer cell migration and angiogenesis. Moreover, our in vivo findings indicated that TAM derived IL-6 induces CSC population and resulting tumor growth in breast cancer. CONCLUSION: These finding provide evidence that TAM derived IL-6 plays a major role in CSC enrichment and tumor progression in breast cancer and IL-6 and its regulated signalling network may act as potential therapeutic target for management of breast cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-022-02527-9.
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spelling pubmed-89321052022-03-23 Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway Radharani, N. N. V. Yadav, Amit S. Nimma, Ramakrishna Kumar, T. V. Santosh Bulbule, Anuradha Chanukuppa, Venkatesh Kumar, Dhiraj Patnaik, Srinivas Rapole, Srikanth Kundu, Gopal C. Cancer Cell Int Primary Research BACKGROUND: Cancer stem cells (CSCs) play crucial role in tumor progression, drug resistance and relapse in various cancers. CSC niche is comprised of various stromal cell types including Tumor-associated macrophages (TAMs). Extrinsic ques derived from these cells help in maintenance of CSC phenotype. TAMs have versatile roles in tumor progression however their function in enrichment of CSC is poorly explored. METHODS: Mouse macrophages (RAW264.7) cells were activated by interaction with conditioned media (CM) of murine breast cancer cells (4T1) into TAMs and the effect of activated macrophage (TAM) derived factors was examined on enrichment of cancer stem cells (CSCs) and tumor growth using in vitro and in vivo models. RESULTS: In this study, we report that macrophages upon interaction with breast cancer cells activate tumor promoting function and exhibit differential expression of various proteins as shown by secretome analysis using proteomics studies. Based on secretome data, we found that Interleukin-6 (IL-6) is one of the up-regulated genes expressed in activated macrophages. Further, we confirm that TAMs produce high levels of IL-6 and breast cancer cell derived factors induce IL-6 production in activated macrophages via p38-MAPK pathway. Furthermore, we demonstrate that tumor activated macrophages induce enrichment of CSCs and expression of CSC specific transcription factors such as Sox-2, Oct-3/4 and Nanog in breast cancer cells. We further prove that TAM derived IL-6 plays a key role in TAM mediated CSC enrichment through activation of Signal transducer and activator of transcription 3 (STAT-3) signaling. TAM derived IL-6 influences breast cancer cell migration and angiogenesis. Moreover, our in vivo findings indicated that TAM derived IL-6 induces CSC population and resulting tumor growth in breast cancer. CONCLUSION: These finding provide evidence that TAM derived IL-6 plays a major role in CSC enrichment and tumor progression in breast cancer and IL-6 and its regulated signalling network may act as potential therapeutic target for management of breast cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-022-02527-9. BioMed Central 2022-03-17 /pmc/articles/PMC8932105/ /pubmed/35300689 http://dx.doi.org/10.1186/s12935-022-02527-9 Text en © The Author(s) 2022 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 Primary Research
Radharani, N. N. V.
Yadav, Amit S.
Nimma, Ramakrishna
Kumar, T. V. Santosh
Bulbule, Anuradha
Chanukuppa, Venkatesh
Kumar, Dhiraj
Patnaik, Srinivas
Rapole, Srikanth
Kundu, Gopal C.
Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway
title Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway
title_full Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway
title_fullStr Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway
title_full_unstemmed Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway
title_short Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway
title_sort tumor-associated macrophage derived il-6 enriches cancer stem cell population and promotes breast tumor progression via stat-3 pathway
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932105/
https://www.ncbi.nlm.nih.gov/pubmed/35300689
http://dx.doi.org/10.1186/s12935-022-02527-9
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