Co-migration of colon cancer cells and CAFs induced by TGFβ₁ enhances liver metastasis
Abstract
Colorectal cancer (CRC) cells often metastatize to the liver. Cancer-associated fibroblasts (CAFs) enhance metastasis by providing cytokines that create a favorable microenvironment and by inducing co-dissemination with tumor cells. However, the mechanisms of co-metastatization remain elusive. The aim of this study is to assess the role of TGFβ1 in CRC cell-CAFs attachment and its impact on liver metastasis. CAFs were obtained after xenotransplantation of Mc38 cells into EGFP-C57BL/6 mice. Attachment experiments with CRC cells and CAFs (with or without TGFβ1 and the inhibitory peptide P17) were carried out, as well as in vivo liver metastasis assays. TGFβ1 induced adhesion of CRC cells to CAFs, whereas exposure to P17 abrogated this effect. Co-injection of Mc38 cells with CAFs intrasplenically increased liver metastasis, as compared to injection of tumor cells alone. Pretreatment of Mc38 cells with TGFβ1 enhanced the metastatic burden, in comparison to untreated Mc38 + CAFs. TGFβ1-pretreated Mc38 cells co-metastatized with CAFs to the liver in a highly efficient way. Importantly, the metastatic burden was significantly reduced (p < 0.001) when P17 was administered in mice. The number of PCNA+ and CD-31+ cells was also reduced by P17 in these animals, indicating a decrease in proliferation and angiogenesis upon TGFβ1 signaling blockade. Through microarray analysis, we identified potential TGFβ1-regulated genes that may mediate cancer cell-stroma interactions to increase metastasis. In conclusion, TGFβ1 promotes co-travelling of CRC cells and CAFs to the liver to enhance metastasis. Our results strongly support the use of TGFβ1 targeted drugs as a novel strategy to reduce liver metastasis in CRC patients.
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Stromal contribution to resistance in CMS4 colorectal cancer occurs through co-migration with cancer cells to metastatic sites.
“co-migration with cancer cells to metastatic sites (70)”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [70]
The prevalent stromal contingent in CMS4 colorectal cancer is likely to contribute to resistance mechanisms.
“In terms of TME contexture, the prevalent stromal contingent is likely to contribute to resistance mechanisms, for instance through ECM deposition and cancer cells insulation (54), co-migration with cancer cells to metastatic sites (70), chemotherapy-induced secretome fostering metastasis, angiogenesis, immune evasion and/or drug resistance (71), or even drug retention, as demonstrated in the case”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [70]
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- Authors
- Gonzalez-Zubeldia, I., Dotor, J., Redrado, M., Bleau, A.-M., Manrique, I., de Aberasturi, A. L., Villalba, M., & Calvo, A.
- Affiliations
- Centro de Investigación Médica Aplicada (ES)
- Corresponding author
- Calvo, Alfonso
- Venue
- Cell and Tissue Research
- Published
- 2015-01-06
- Volume
- 359
- Issue
- 3
- Pages
- 829-839
- ISSN
- 0302-766X (ISSN-L)
- 1432-0878
- OpenAlex
- W1967262045
- Cited by
- 51
- References
- 30
- Citations by year
- 2025: 2 · 2024: 6 · 2023: 5 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 6 · 2015: 2
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell and Tissue Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministerio de Economía y Competitividad
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- colorectal cancer, liver metastasis, cancer-associated fibroblasts, TGF-β1, tumor microenvironment, angiogenesis, cell proliferation
- MeSH terms
- Animals, Cell Adhesion, Cell Movement, Colonic Neoplasms, Extracellular Matrix, Fibroblasts, Fluorescent Antibody Technique, Liver Neoplasms, Mice, Inbred C57BL, Gene Expression Regulation, Neoplastic, Endothelial Cells, Cell Line, Tumor, Green Fluorescent Proteins, Transforming Growth Factor beta1
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