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Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer
BACKGROUND: The tumor microenvironment has a critical role in regulating cancer cell behavior. Tumors with high stromal content are associated with poor patient outcome. The tumor-stroma ratio (TSR) identifies colorectal cancers (CRC) with poor patient prognosis based on hematoxylin & eosin stai...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440123/ https://www.ncbi.nlm.nih.gov/pubmed/30922247 http://dx.doi.org/10.1186/s12885-019-5462-2 |
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author | Sandberg, Tessa P. Stuart, Maaike P. M. E. Oosting, Jan Tollenaar, Rob A. E. M. Sier, Cornelis F. M. Mesker, Wilma E. |
author_facet | Sandberg, Tessa P. Stuart, Maaike P. M. E. Oosting, Jan Tollenaar, Rob A. E. M. Sier, Cornelis F. M. Mesker, Wilma E. |
author_sort | Sandberg, Tessa P. |
collection | PubMed |
description | BACKGROUND: The tumor microenvironment has a critical role in regulating cancer cell behavior. Tumors with high stromal content are associated with poor patient outcome. The tumor-stroma ratio (TSR) identifies colorectal cancers (CRC) with poor patient prognosis based on hematoxylin & eosin stained sections. The desmoplastic reaction consists to a great extent of cancer-associated fibroblasts (CAFs) of which different subtypes are known. The aim of this study is to investigate and quantify CAFs present in the tumor stroma of CRC stratified by the TSR to possibly add prognostic significance to the TSR. METHODS: The expression of established CAF markers was compared between stroma-low and stroma-high tumors using transcriptomic data of 71 stage I – III CRC. Based on literature, fibroblast and stromal markers were selected to perform multiplex immunofluorescent staining on formalin fixed, paraffin-embedded tumor sections of patients diagnosed with stage III colon cancer. Antibodies against the following markers were used: αSMA, PDGFR -β, FAP, FSP1 and the stromal markers CD45 and CD31 as reference. The markers were subsequently quantified in the stroma using the Vectra imaging microscope. RESULTS: The transcriptomic data showed that all CAF markers except one were higher expressed in stroma-high compared to stroma-low tumors. Histologically, stroma-high tumors showed a decreased number of FSP1(+)/CD45(+) cells and a trend of an increased expression of FAP compared to stroma-low tumors. FAP was higher expressed at the invasive part compared to the tumor center in both stroma-high and stroma-low tumors. CONCLUSIONS: The increased expression of FAP at the invasive part and in stroma-high tumors might contribute to the invasive behavior of cancer cells. Future functional experiments should investigate the contribution of FAP to cancer cell invasion. Combining the quantity of the stroma as defined by the TSR with the activity level of CAFs using the expression of FAP may result in an expanded stroma-based tool for patient stratification. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5462-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6440123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-64401232019-04-11 Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer Sandberg, Tessa P. Stuart, Maaike P. M. E. Oosting, Jan Tollenaar, Rob A. E. M. Sier, Cornelis F. M. Mesker, Wilma E. BMC Cancer Research Article BACKGROUND: The tumor microenvironment has a critical role in regulating cancer cell behavior. Tumors with high stromal content are associated with poor patient outcome. The tumor-stroma ratio (TSR) identifies colorectal cancers (CRC) with poor patient prognosis based on hematoxylin & eosin stained sections. The desmoplastic reaction consists to a great extent of cancer-associated fibroblasts (CAFs) of which different subtypes are known. The aim of this study is to investigate and quantify CAFs present in the tumor stroma of CRC stratified by the TSR to possibly add prognostic significance to the TSR. METHODS: The expression of established CAF markers was compared between stroma-low and stroma-high tumors using transcriptomic data of 71 stage I – III CRC. Based on literature, fibroblast and stromal markers were selected to perform multiplex immunofluorescent staining on formalin fixed, paraffin-embedded tumor sections of patients diagnosed with stage III colon cancer. Antibodies against the following markers were used: αSMA, PDGFR -β, FAP, FSP1 and the stromal markers CD45 and CD31 as reference. The markers were subsequently quantified in the stroma using the Vectra imaging microscope. RESULTS: The transcriptomic data showed that all CAF markers except one were higher expressed in stroma-high compared to stroma-low tumors. Histologically, stroma-high tumors showed a decreased number of FSP1(+)/CD45(+) cells and a trend of an increased expression of FAP compared to stroma-low tumors. FAP was higher expressed at the invasive part compared to the tumor center in both stroma-high and stroma-low tumors. CONCLUSIONS: The increased expression of FAP at the invasive part and in stroma-high tumors might contribute to the invasive behavior of cancer cells. Future functional experiments should investigate the contribution of FAP to cancer cell invasion. Combining the quantity of the stroma as defined by the TSR with the activity level of CAFs using the expression of FAP may result in an expanded stroma-based tool for patient stratification. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5462-2) contains supplementary material, which is available to authorized users. BioMed Central 2019-03-29 /pmc/articles/PMC6440123/ /pubmed/30922247 http://dx.doi.org/10.1186/s12885-019-5462-2 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Sandberg, Tessa P. Stuart, Maaike P. M. E. Oosting, Jan Tollenaar, Rob A. E. M. Sier, Cornelis F. M. Mesker, Wilma E. Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer |
title | Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer |
title_full | Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer |
title_fullStr | Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer |
title_full_unstemmed | Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer |
title_short | Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer |
title_sort | increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440123/ https://www.ncbi.nlm.nih.gov/pubmed/30922247 http://dx.doi.org/10.1186/s12885-019-5462-2 |
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