Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15
Published version of a preprint
Abstract
The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGFβ/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. Cancer Res; 74(13); 3408–17. ©2014 AACR.
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Production of TGFβ, LIF, GAS6, FGF5, GDF15 and HGF promotes invasive and proliferative behaviour in cancer cells.
“The production of TGFβ, leukaemia inhibitory factor (LIF), growth arrest-specific protein 6 (GAS6), fibroblast growth factor 5 (FGF5), growth differentiation factor 15 (GDF15) and hepatocyte growth factor (HGF) promotes invasive and proliferative behaviour in cancer cells52,109–112.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [112]
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- Authors
- Bruzzese, F., Hägglöf, C., Leone, A., Sjöberg, E., Roca, M. S., Kiflemariam, S., Sjöblom, T., Hammarsten, P., Egevad, L., Bergh, A., Östman, A., Budillon, A., & Augsten, M.
- Affiliations
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- Umeå University (SE)
- Karolinska Institutet (SE)
- Uppsala University (SE)
- Corresponding author
- Augsten, Martin
- ORCID
- Venue
- Cancer Research
- Published
- 2014-06-30
- Volume
- 74
- Issue
- 13
- Pages
- 3408-3417
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W1967708173
- Cited by
- 127
- References
- 4
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 9 · 2023: 12 · 2022: 8 · 2021: 15 · 2020: 19 · 2019: 9 · 2018: 11 · 2017: 10 · 2016: 9 · 2015: 8 · 2014: 1
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancerfonden
- Lunds Universitet
- Vetenskapsrådet
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- GDF15, MIC-1, cancer-associated fibroblasts, prostate cancer, tumor microenvironment, tumor stroma, paracrine signaling, tumor progression, metastasis, tumor growth, tumor markers, therapeutic target
- MeSH terms
- Animals, Cell Movement, Cell Transformation, Neoplastic, Fibroblasts, Humans, Male, Neoplasm Invasiveness, Neoplasm Transplantation, Prostatic Neoplasms, Biomarkers, Tumor, Up-Regulation, Gene Expression Regulation, Neoplastic, 3T3 Cells, Mice, SCID, Cell Line, Tumor, Cell Proliferation, Mice, Growth Differentiation Factor 15, Tumor Microenvironment, Heterografts
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