Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal CancerSummary
Background & Aims: Improving clinical management of early stage colorectal cancers (T1CRCs) requires a better understanding of their underlying biology. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) are important determinants of tumor progression in advanced colorecta...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X23000553 |
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| author | Hao Dang Tom J. Harryvan Chen-Yi Liao Erik H.J. Danen Vienna N.L.N. Spalburg Szymon M. Kielbasa Hailiang Mei Jelle J. Goeman Eveline S. de Jonge-Muller Stefanus G.T. Janson Johan J. van der Reijden Stijn Crobach James C.H. Hardwick Jurjen J. Boonstra Noel F.C.C. de Miranda Lukas J.A.C. Hawinkels |
| author_facet | Hao Dang Tom J. Harryvan Chen-Yi Liao Erik H.J. Danen Vienna N.L.N. Spalburg Szymon M. Kielbasa Hailiang Mei Jelle J. Goeman Eveline S. de Jonge-Muller Stefanus G.T. Janson Johan J. van der Reijden Stijn Crobach James C.H. Hardwick Jurjen J. Boonstra Noel F.C.C. de Miranda Lukas J.A.C. Hawinkels |
| author_sort | Hao Dang |
| collection | DOAJ |
| description | Background & Aims: Improving clinical management of early stage colorectal cancers (T1CRCs) requires a better understanding of their underlying biology. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) are important determinants of tumor progression in advanced colorectal cancer (CRC), but their role in the initial stages of CRC tumorigenesis is unknown. Therefore, we investigated the contribution of T1CAFs to early CRC progression. Methods: Primary T1CAFs and patient-matched normal fibroblasts (NFs) were isolated from endoscopic biopsy specimens of histologically confirmed T1CRCs and normal mucosa, respectively. The impact of T1CAFs and NFs on tumor behavior was studied using 3-dimensional co-culture systems with primary T1CRC organoids and extracellular matrix (ECM) remodeling assays. Whole-transcriptome sequencing and gene silencing were used to pinpoint mediators of T1CAF functions. Results: In 3-dimensional multicellular cultures, matrix invasion of T1CRC organoids was induced by T1CAFs, but not by matched NFs. Enhanced T1CRC invasion was accompanied by T1CAF-induced ECM remodeling and up-regulation of CD44 in epithelial cells. RNA sequencing of 10 NF-T1CAF pairs revealed 404 differentially expressed genes, with significant enrichment for ECM-related pathways in T1CAFs. Cathepsin H, a cysteine-type protease that was specifically up-regulated in T1CAFs but not in fibroblasts from premalignant lesions or advanced CRCs, was identified as a key factor driving matrix remodeling by T1CAFs. Finally, we showed high abundance of cathepsin H–expressing T1CAFs at the invasive front of primary T1CRC sections. Conclusions: Already in the earliest stage of CRC, cancer cell invasion is promoted by CAFs via direct interactions with epithelial cancer cells and stage-specific, cathepsin H–dependent ECM remodeling. RNA sequencing data of the 10 NF-T1CAF pairs can be found under GEO accession number GSE200660. |
| first_indexed | 2024-03-13T09:41:50Z |
| format | Article |
| id | doaj.art-c17384556e2f4239824a3eadd4ee6a6a |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-03-13T09:41:50Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-c17384556e2f4239824a3eadd4ee6a6a2023-05-25T04:24:32ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2023-01-01161107131Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal CancerSummaryHao Dang0Tom J. Harryvan1Chen-Yi Liao2Erik H.J. Danen3Vienna N.L.N. Spalburg4Szymon M. Kielbasa5Hailiang Mei6Jelle J. Goeman7Eveline S. de Jonge-Muller8Stefanus G.T. Janson9Johan J. van der Reijden10Stijn Crobach11James C.H. Hardwick12Jurjen J. Boonstra13Noel F.C.C. de Miranda14Lukas J.A.C. Hawinkels15Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsDivision of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The NetherlandsDivision of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Pathology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Pathology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; Correspondence Address correspondence to: Lukas J. A. C. Hawinkels, PhD, Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.Background & Aims: Improving clinical management of early stage colorectal cancers (T1CRCs) requires a better understanding of their underlying biology. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) are important determinants of tumor progression in advanced colorectal cancer (CRC), but their role in the initial stages of CRC tumorigenesis is unknown. Therefore, we investigated the contribution of T1CAFs to early CRC progression. Methods: Primary T1CAFs and patient-matched normal fibroblasts (NFs) were isolated from endoscopic biopsy specimens of histologically confirmed T1CRCs and normal mucosa, respectively. The impact of T1CAFs and NFs on tumor behavior was studied using 3-dimensional co-culture systems with primary T1CRC organoids and extracellular matrix (ECM) remodeling assays. Whole-transcriptome sequencing and gene silencing were used to pinpoint mediators of T1CAF functions. Results: In 3-dimensional multicellular cultures, matrix invasion of T1CRC organoids was induced by T1CAFs, but not by matched NFs. Enhanced T1CRC invasion was accompanied by T1CAF-induced ECM remodeling and up-regulation of CD44 in epithelial cells. RNA sequencing of 10 NF-T1CAF pairs revealed 404 differentially expressed genes, with significant enrichment for ECM-related pathways in T1CAFs. Cathepsin H, a cysteine-type protease that was specifically up-regulated in T1CAFs but not in fibroblasts from premalignant lesions or advanced CRCs, was identified as a key factor driving matrix remodeling by T1CAFs. Finally, we showed high abundance of cathepsin H–expressing T1CAFs at the invasive front of primary T1CRC sections. Conclusions: Already in the earliest stage of CRC, cancer cell invasion is promoted by CAFs via direct interactions with epithelial cancer cells and stage-specific, cathepsin H–dependent ECM remodeling. RNA sequencing data of the 10 NF-T1CAF pairs can be found under GEO accession number GSE200660.http://www.sciencedirect.com/science/article/pii/S2352345X23000553T1 Colorectal CancerTumor MicroenvironmentCancer-Associated Fibroblast |
| spellingShingle | Hao Dang Tom J. Harryvan Chen-Yi Liao Erik H.J. Danen Vienna N.L.N. Spalburg Szymon M. Kielbasa Hailiang Mei Jelle J. Goeman Eveline S. de Jonge-Muller Stefanus G.T. Janson Johan J. van der Reijden Stijn Crobach James C.H. Hardwick Jurjen J. Boonstra Noel F.C.C. de Miranda Lukas J.A.C. Hawinkels Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal CancerSummary Cellular and Molecular Gastroenterology and Hepatology T1 Colorectal Cancer Tumor Microenvironment Cancer-Associated Fibroblast |
| title | Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal CancerSummary |
| title_full | Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal CancerSummary |
| title_fullStr | Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal CancerSummary |
| title_full_unstemmed | Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal CancerSummary |
| title_short | Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal CancerSummary |
| title_sort | cancer associated fibroblasts are key determinants of cancer cell invasion in the earliest stage of colorectal cancersummary |
| topic | T1 Colorectal Cancer Tumor Microenvironment Cancer-Associated Fibroblast |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X23000553 |
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