Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
Open accessAbstract
A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.
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CAFs are able to boost metastasis in experimental models, and this correlated with their ability to remodel the ECM.
“In addition to promoting local invasion, CAFs are able to boost metastasis in experimental models, and this correlated with their ability to remodel the ECM91–93.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [93]
The Abstract and Results report that TGF-β-stimulated CAFs support colorectal cancer metastasis initiation in experimental models. The Results also describe an enhanced desmoplastic reaction in metastases, but do not establish that the metastatic boost correlated with CAFs’ ability to remodel the ECM. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCAFs can help define the immunosuppressive environment, through effects on immune cell activation and impeding infiltration of immune cells into tumors.
“Additionally, they can help define the immunosuppressive environment, through effects on immune cell activation and impeding infiltration of immune cells into tumors227–231.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [230]
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- Authors
- Calon, A., Espinet, E., Palomo-Ponce, S., Tauriello, D. V. F., Iglesias, M., Céspedes, M. V., Sevillano, M., Nadal, C., Jung, P., Zhang, X. H.-F., Byrom, D., Riera, A., Rossell, D., Mangues, R., Massagué, J., Sancho, E., & Batlle, E.
- Affiliations
- Institute for Research in Biomedicine (ES)
- Universitat Autònoma de Barcelona (ES)
- Hospital de Sant Pau (ES)
- Hospital Clínic de Barcelona (ES)
- Memorial Sloan Kettering Cancer Center (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Sancho, Elena
- Batlle, Eduard
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 22
- Issue
- 5
- Pages
- 571-584
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3512565
- OpenAlex
- W2171352366
- Cited by
- 1,060
- References
- 52
- Citations by year
- 2026: 42 · 2025: 64 · 2024: 58 · 2023: 92 · 2022: 99 · 2021: 116 · 2020: 104 · 2019: 90 · 2018: 73 · 2017: 75 · 2016: 76 · 2015: 74 · 2014: 58 · 2013: 34 · 2012: 3
- FWCI
- 21.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 377 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Instituto de Salud Carlos III (RD09/0076/00036)
- Ministerio de Ciencia e Innovación (SAF2006-02170, SAF2009-11757)
- National Institutes of Health (CA34610)
- Fundación BBVA (PS09/00965)
- European Research Council (208488)
- Family Process Institute
- 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, TGF-beta signaling, tumor stroma, cancer-associated fibroblasts, metastasis initiation, interleukin-11, tumor microenvironment, tumor recurrence, organ colonization
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Animals, Humans, Neoplasm Metastasis, Recurrence, Tumor Cells, Cultured, Colorectal Neoplasms, Signal Transduction, Transforming Growth Factor beta, Stromal Cells, Protein Serine-Threonine Kinases, Interleukin-11, Receptors, Transforming Growth Factor beta, HT29 Cells, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice, Tumor Microenvironment
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