Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells
Open accessAbstract
BACKGROUND: Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity. METHODS: We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test. RESULTS: We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03). CONCLUSIONS: Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.
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Therapeutic targets involving pericytes may exacerbate tumor metastasis.
“others indicated that therapeutic targets involving pericytes may exacerbate the process of tumor metastasis [31–34].”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [33]
The Results (page not provided) report more circulating malignant cells in pericyte-deficient mice bearing B16 tumors, supporting concern that loss of pericytes could aid tumor-cell dissemination. The study used genetic pericyte deficiency, not a pericyte-targeting therapy, and did not establish increased metastasis; the claim extends beyond those findings. (LLM, conf=0.85)
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- Authors
- Hong, J., Tobin, N. P., Rundqvist, H., Li, T., Lavergne, M., García-Ibáñez, Y., Qin, H., Paulsson, J., Zeitelhofer, M., Adzemovic, M. Z., Nilsson, I., Roswall, P., Hartman, J., Johnson, R. S., Östman, A., Bergh, J., Poljakovic, M., & Genové, G.
- Affiliations
- Karolinska University Hospital (SE)
- ORCID
- Venue
- Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-08-21
- Volume
- 107
- Issue
- 10
- Pages
- djv209
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC6592827
- OpenAlex
- W2114137950
- Cited by
- 75
- References
- 42
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 1 · 2018: 10 · 2017: 7 · 2016: 10 · 2015: 1
- FWCI
- 4.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (092738/Z/10/Z, 092738)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- myeloid-derived suppressor cells, tumor vasculature, tumor hypoxia, interleukin-6, leukocyte transmigration, breast cancer, CD33, S100A9, prognosis, tumor microenvironment, paracrine signaling
- MeSH terms
- Animals, Antigens, Surface, Breast Neoplasms, Cell Movement, Female, Flow Cytometry, Humans, Neoplasms, Experimental, Sweden, Cell Hypoxia, Interleukin-6, Receptors, Chemokine, Pericytes, Gene Silencing, Myeloid Cells, CD11b Antigen, Subcutaneous Tissue, Mice, Tumor Microenvironment, Transcriptome
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