| Autor: |
Claudia Tulotta, Diane V. Lefley, Charlotte K. Moore, Ana E. Amariutei, Amy R. Spicer-Hadlington, Lewis A. Quayle, Russell O. Hughes, Khawla Ahmed, Victoria Cookson, Catherine A. Evans, Jayakumar Vadakekolathu, Paul Heath, Sheila Francis, Emmanuel Pinteaux, A. Graham Pockley, Penelope D. Ottewell |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
npj Breast Cancer, Vol 7, Iss 1, Pp 1-15 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2374-4677 |
| DOI: |
10.1038/s41523-021-00305-w |
| Popis: |
Abstract Breast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast cancer develop disease recurrence in bone and available treatments are only palliative. We have previously shown that production of the pro-inflammatory cytokine interleukin-1B (IL-1B) by breast cancer cells drives bone metastasis in patients and in preclinical in vivo models. In the current study, we have investigated how IL-1B from tumour cells and the microenvironment interact to affect primary tumour growth and bone metastasis through regulation of the immune system, and whether targeting IL-1 driven changes to the immune response improves standard of care therapy for breast cancer bone metastasis. Using syngeneic IL-1B/IL1R1 knock out mouse models in combination with genetic manipulation of tumour cells to overexpress IL-1B/IL1R1, we found that IL-1B signalling elicited an opposite response in primary tumours compared with bone metastases. In primary tumours, IL-1B inhibited growth, by impairing the infiltration of innate immune cell subsets with potential anti-cancer functions but promoted enhanced tumour cell migration. In bone, IL-1B stimulated the development of osteolytic metastases. In syngeneic models of breast cancer, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited both primary tumour growth and metastasis. Anakinra had opposite effects on the immune response compared to standard of care treatment, and its anti-inflammatory signature was maintained in the combination therapy. These data suggest that targeting IL-1B signalling may provide a useful therapeutic approach to inhibit bone metastasis and improve efficacy of current treatments for breast cancer patients. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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