Cited by 177Chemokine receptors and signalingCancer Cells and MetastasisCytokine Signaling Pathways and Interactions

Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration

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Jayatilaka, Hasini, Tyle, Pranay, Chen, Jonathan J., Kwak, Minsuk, Ju, Julia, Kim, Hyun Ji, Lee, Jerry S. H., Wu, Pei-Hsun +3 more·2017·Nature Communications

Abstract

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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Crossref · 10.1038/ncomms15584

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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].”

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Research works printed but not linked: 2

  1. Lou W., Ni Z., Dyer K., Tweardy D. J. & Gao A. C. Interleukin-6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway. Prostate 42, 239– 242 (2000). 10639195
  2. Guo S.. Nonstochastic reprogramming from a privileged somatic cell state. Cell 156, 649– 662 (2014). 24486105 PMC4318260

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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
Venue
Nature Communications
Published
2017-05-26
Volume
8
Issue
1
Pages
15584-15584
ISSN
2041-1723 (ISSN-L)
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
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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