Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast Cancer Model
Open accessAbstract
BACKGROUND: Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+) T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.
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Paracrine signals from cancer cells can recruit and activate CAFs within the TME.
“Accumulating evidence suggests that paracrine signals from cancer cells can both recruit and activate CAFs within the TME, and contribute to their activation (Whiteside, 2008; Liao et al., 2009; Orimo et al., 2005; Chung et al., 2006).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Liao et al., 2009
CAFs have been shown to regulate cancer cell growth.
“Since CAFs have been shown to regulate cancer cell growth (Liao et al., 2009)”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Liao et al., 2009
CAF depletion in the TME leads to a shift from Th2 to Th1 to promote inflammation, accompanied by up-regulation of IL-2 and IL-7 and downregulation of TAMs, Tregs and MDSCs.
“CAF depletion in the TME leads to a shift from T helper 2 (Th2) to T helper 1 (Th1) to promote inflammation, accompanied by the up‐regulation of IL‐2 and IL‐7 and downregulation of TAMs, Tregs and MDSCs [101].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [101]
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- Authors
- Liao, D., Luo, Y., Markowitz, D., Xiang, R., & Reisfeld, R. A.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Reisfeld, Ralph A.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-11-23
- Volume
- 4
- Issue
- 11
- Pages
- e7965
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2775953
- OpenAlex
- W1995481385
- Cited by
- 437
- References
- 47
- Citations by year
- 2026: 4 · 2025: 17 · 2024: 14 · 2023: 23 · 2022: 27 · 2021: 28 · 2020: 35 · 2019: 28 · 2018: 26 · 2017: 31 · 2016: 29 · 2015: 26 · 2014: 38 · 2013: 35 · 2012: 32
- FWCI
- 10.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense
- National Natural Science Foundation of China (2007CB914804, 973 Program, 30672389)
- Thailand Science Research and Innovation
- National Institutes of Health
- National High-tech Research and Development Program
- National Key Research and Development Program of China (2007CB914804)
- National Heart, Lung, and Blood Institute (T32HL007195)
- National Cancer Institute (BC050141)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- cancer-associated fibroblasts, metastatic breast cancer, tumor immune microenvironment, immune polarization, Th1/Th2 shift, fibroblast activation protein, DNA vaccine, tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, tumor angiogenesis, lymphangiogenesis, doxorubicin combination therapy, dendritic cells, CD8+ T cells
- MeSH terms
- Animals, Female, Fibroblasts, Interleukin-2, Lymphokines, Mice, Inbred BALB C, Neoplasm Metastasis, Platelet-Derived Growth Factor, Interleukin-7, Granulocyte-Macrophage Colony-Stimulating Factor, CD8-Positive T-Lymphocytes, Th1 Cells, Th2 Cells, Disease Progression, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice
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