Tulotta, C., Lefley, D.V., Freeman, K. et al. (16 more authors) (2019) Endogenous production of IL-1B by breast cancer cells drives metastasis and colonisation of the bone microenvironment. Clinical Cancer Research, 25 (9). pp. 2769-2782. ISSN 1078-0432
Abstract
BACKGROUND: Breast cancer bone metastases are incurable highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL-1B by tumor cells drives metastasis and growth in bone. METHODS: Tumor/stromal IL-B and IL-1R1 expression was assessed in patient samples and effects of the IL-1R antagonist, Anakinra or the IL-1B antibody Canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell-derived IL-1B on bone colonisation and parameters associated with metastasis were measured in MDA-MB-231, MCF7 and T47D cells transfected with IL-1B/control. RESULTS: In tissue samples from >1300 patients with stage II/III breast cancer, IL-1B in tumor cells correlated with relapse in bone (hazard ratio 1.85; 95% CI 1.05-3.26; P=0.02) and other sites (hazard ratio 2.09; 95% CI 1.26-3.48; P=0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or Canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL-1B by tumor cells promoted EMT (altered E-Cadherin, N-Cadherin and G-Catenin), invasion, migration and bone colonisation. Contact between tumor and osteoblasts or bone marrow cells increased IL-1B secretion from all three cell types. IL-1B alone did not stimulate tumor cell proliferation. Instead, IL-1B caused expansion of the bone metastatic niche leading to tumor proliferation. CONCLUSION: Pharmacological inhibition of IL-1B has potential as a novel treatment for breast cancer metastasis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 American Association for Cancer Research. This is an author-produced version of a paper accepted for publication in Clinical Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Breast cancer; Bone metastasis; IL-1B; bone metastatic niche; biomarker; Canakinumab; IL-1R antagonist |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number CANCER RESEARCH UK UNSPECIFIED WESTON PARK HOSPITAL CANCER CHARITY CA143 MEDICAL RESEARCH COUNCIL MR/P000096/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 31 Jan 2019 15:17 |
Last Modified: | 16 Nov 2021 14:01 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Refereed: | Yes |
Identification Number: | 10.1158/1078-0432.CCR-18-2202 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:141871 |