Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration
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Following uncontrolled proliferation, a subset of primary tumour cells acquires additional traits/mutations to trigger phenotypic changes that enhance migration and are hypothesized to be the initiators of metastasis. This study reveals an adaptive mechanism that harnesses synergistic paracrine signalling via IL-6/8, which is amplified by cell proliferation and cell density, to directly promote cell migration. This effect occurs in metastatic human sarcoma and carcinoma cells- but not in normal or non-metastatic cancer cells-, and likely involves the downstream signalling of WASF3 and Arp2/3. The transcriptional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells treated with a combination of IL-6/8. Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis. This study reveals a potential mechanism that promotes tumour cell migration and infers a strategy to decrease metastatic capacity of tumour cells.
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Simultaneous inhibition of the IL-6 receptor using tocilizumab and the IL-8 receptor by reparixin showed significantly decreased metastasis of breast cancer cells to the lung, liver, and lymph nodes in a mouse mammary xenograft model.
“First promising anti-cancer efficacy was recently provided by the simultaneous inhibition of the IL-6 receptor using tocilizumab and the IL-8 receptor by reparixin, showing significantly decreased metastasis of breast cancer cells to the lung, liver, and lymph nodes in a mouse mammary xenograft model [85].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [85]
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- Authors
- Jayatilaka, H., Tyle, P., Chen, J. J., Kwak, M., Ju, J., Kim, H. J., Lee, J. S. H., Wu, P.-H., Gilkes, D. M., Fan, R., & Wirtz, D.
- Affiliations
- Johns Hopkins University (US)
- Yale University (US)
- Corresponding author
- Gilkes, Daniele M.
- Fan, Rong
- Wirtz, Denis
- ORCID
- Venue
- Nature Communications
- Published
- 2017-05-26
- Volume
- 8
- Issue
- 1
- Pages
- 15584-15584
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5458548
- OpenAlex
- W2620210866
- Cited by
- 177
- References
- 63
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 16 · 2023: 19 · 2022: 30 · 2021: 22 · 2020: 20 · 2019: 18 · 2018: 24 · 2017: 5
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (R01CA174388, U54CA193461, R00CA181352, U54CA210173)
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-6, interleukin-8, paracrine signaling, tumor cell migration, metastasis, sarcoma, carcinoma, WASF3, Arp2/3 complex, cell density, cell proliferation, tumor microenvironment, xenograft models, metastasis suppression
- MeSH terms
- Animals, Antineoplastic Agents, Carcinoma, Cell Movement, Humans, Neoplasm Invasiveness, Sarcoma, Sulfonamides, Signal Transduction, Interleukin-6, Interleukin-8, Mice, SCID, Mice, Inbred NOD, Paracrine Communication, Receptors, Interleukin-6, Xenograft Model Antitumor Assays, Receptors, Interleukin-8A, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Wiskott-Aldrich Syndrome Protein Family, Actin-Related Protein 2-3 Complex, Mice, Molecular Targeted Therapy, Antibodies, Monoclonal, Humanized
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