Endogenous Production of IL1B by Breast Cancer Cells Drives Metastasis and Colonization of the Bone Microenvironment.
- Tulotta C Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Lefley DV Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Freeman K Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Gregory WM Leeds Institute of Clinical Trials Research, Leeds, United Kingdom.
- Hanby AM Institute of Molecular Medicine, St James's University Hospital, Leeds, United Kingdom.
- Heath PR Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom.
- Nutter F Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Wilkinson JM Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Spicer-Hadlington AR Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Liu X Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Bradbury SMJ Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Hambley L Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Cookson V Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Allocca G Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Kruithof de Julio M Department of Biomedical Research, University of Bern, Bern, Switzerland.
- Coleman RE Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Brown JE Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Holen I Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
- Ottewell PD Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom. p.d.ottewell@sheffield.ac.uk.
- 2019-01-24
Published in:
- Clinical cancer research : an official journal of the American Association for Cancer Research. - 2019
Aged
Animals
Apoptosis
Bone Neoplasms
Breast Neoplasms
Case-Control Studies
Cell Proliferation
Epithelial-Mesenchymal Transition
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Interleukin-1beta
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
Prognosis
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
English
PURPOSE
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 IL1B by tumor cells drives metastasis and growth in bone.
EXPERIMENTAL DESIGN
Tumor/stromal IL1B and IL1 receptor 1 (IL1R1) expression was assessed in patient samples and effects of the IL1R antagonist, Anakinra, or the IL1B 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 IL1B on bone colonization and parameters associated with metastasis were measured in MDA-MB-231, MCF7, and T47D cells transfected with IL1B/control.
RESULTS
In tissue samples from >1,300 patients with stage II/III breast cancer, IL1B in tumor cells correlated with relapse in bone (HR = 1.85; 95% CI, 1.05-3.26; P = 0.02) and other sites (HR = 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 IL1B by tumor cells promoted epithelial-to-mesenchymal transition (altered E-Cadherin, N-Cadherin, and G-Catenin), invasion, migration, and bone colonization. Contact between tumor and osteoblasts or bone marrow cells increased IL1B secretion from all three cell types. IL1B alone did not stimulate tumor cell proliferation. Instead, IL1B caused expansion of the bone metastatic niche leading to tumor proliferation.
CONCLUSIONS
Pharmacologic inhibition of IL1B has potential as a novel treatment for breast cancer metastasis.
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 IL1B by tumor cells drives metastasis and growth in bone.
EXPERIMENTAL DESIGN
Tumor/stromal IL1B and IL1 receptor 1 (IL1R1) expression was assessed in patient samples and effects of the IL1R antagonist, Anakinra, or the IL1B 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 IL1B on bone colonization and parameters associated with metastasis were measured in MDA-MB-231, MCF7, and T47D cells transfected with IL1B/control.
RESULTS
In tissue samples from >1,300 patients with stage II/III breast cancer, IL1B in tumor cells correlated with relapse in bone (HR = 1.85; 95% CI, 1.05-3.26; P = 0.02) and other sites (HR = 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 IL1B by tumor cells promoted epithelial-to-mesenchymal transition (altered E-Cadherin, N-Cadherin, and G-Catenin), invasion, migration, and bone colonization. Contact between tumor and osteoblasts or bone marrow cells increased IL1B secretion from all three cell types. IL1B alone did not stimulate tumor cell proliferation. Instead, IL1B caused expansion of the bone metastatic niche leading to tumor proliferation.
CONCLUSIONS
Pharmacologic inhibition of IL1B has potential as a novel treatment for breast cancer metastasis.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1158/1078-0432.CCR-18-2202
- PMID 30670488
- Persistent URL
- https://sonar.ch/global/documents/170287
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