IL-1 drives breast cancer growth and bone metastasis<i>in vivo</i>

Holen, Ingunn; Lefley, Diane V.; Francis, Sheila; Rennicks, Sarah; Bradbury, Steven M.J.; Coleman, Robert E.; Ottewell, Penelope D.

doi:10.18632/oncotarget.12289

Cited by 174 publications

(160 citation statements)

References 39 publications

(51 reference statements)

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“…Although further studies are warranted, it is interesting to speculate that IL‐1/IL‐1R inhibitors may prevent accumulation of tumour‐associated myeloid cells, improving outcome. Although there are inherent problems with IL‐1R blockade, inhibition of IL‐1β has shown promising results in animal models of several cancers …”

Section: Discussionmentioning

confidence: 99%

“…Although there are inherent problems with IL-1R blockade, inhibition of IL-1β has shown promising results in animal models of several cancers. 43,44 Whilst chemokines driving myeloid cell infiltration appear to promote tumour progression, there is evidence that recruitment of certain T-cell populations is associated with improved prognosis. Indeed, in a prospective study, the presence of elevated levels of tumour-infiltrating CD8+ T-cells correlated with a good prognosis in HPV-positive compared to HPV-negative OPC.…”

Section: Discussionmentioning

confidence: 99%

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The IL‐1/IL‐1R axis induces greater fibroblast‐derived chemokine release in human papillomavirus‐negative compared to positive oropharyngeal cancer

Al-Sahaf

Hunter

Bolt

et al. 2018

Intl Journal of Cancer

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Human papillomavirus (HPV) is now recognised as a major aetiological agent in the pathogenesis of oropharyngeal carcinoma (OPC). HPV-positive tumours are associated with better outcomes compared to HPV-negative tumours, possibly due to differences in their aetiology and/or the tumour microenvironment. Increased numbers of tumour-associated leukocytes have been observed in many cancers including OPC, with variable influence on prognosis depending on the leukocyte subpopulation investigated. Whether HPV status influences leukocyte recruitment to OPC remains unknown. This in-vitro study examined differences in the chemoattractant capacity of HPV-positive and HPV-negative OPC cell lines. Gene and protein expression analysis demonstrated that whilst both monocultures of HPV-positive and HPV-negative cell lines, along with normal tonsillar fibroblasts (NTF), expressed low chemokine levels, NTF cultured with conditioned medium from HPV-negative OPC cells expressed significantly higher levels of all chemokines tested compared to NTF incubated with the medium from HPV-positive OPC cell lines. HPV-negative OPC lines expressed IL-1β mRNA whereas HPV-positive cells did not, and NTF constitutively expressed IL-1R1. Pre-treatment with the IL-R antagonist, anakinra or siRNA to IL-1R1 significantly reduced chemokine secretion from NTF stimulated with conditioned medium from HPV-negative tumour cells or recombinant IL-1β (p < 0.05). These data suggest that secretion of chemokines is driven by the interaction between HPV-negative OPC cells and stromal fibroblasts through an IL-1/IL-1R-mediated mechanism that is less prominent within the HPV-positive tumour microenvironment. These observations may explain differences in leukocyte sub-populations recruited to HPV-positive versus negative OPC and indicate that HPV status is a key determinant in controlling the inflammatory tumour microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The IL‐1/IL‐1R axis induces greater fibroblast‐derived chemokine release in human papillomavirus‐negative compared to positive oropharyngeal cancer

Al-Sahaf

Hunter

Bolt

et al. 2018

Intl Journal of Cancer

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“…Having established that the CBFβ-depleted cells retain the ability to form localised tumours but have a restricted capacity to grow in osteoblast culture we next tested their ability to establish bone metastases after injection into the circulation by intracardiac injection (Fig. 5D) 30 .…”

Section: Cbfβ Contributes To the Development Of Bone Metastasis In Micementioning

confidence: 99%

RUNX/CBFβ transcription factor complexes promote the phenotypic plasticity of metastatic breast cancer cells

Ran¹,

Harrison²,

Ariffin³

et al. 2019

Preprint

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Epithelial to mesenchymal transition (EMT) is a dynamic process that drives cancer cell plasticity and is thought to play a major role in metastasis. Here we show that the plasticity of metastatic breast cancer cells can be promoted by the activity of the RUNX transcription factors. We demonstrate that the RUNX co-regulator CBFβ is essential to maintain the mesenchymal phenotype of triple-negative breast cancer cells and that CBFβ-depleted cells undergo a mesenchymal to epithelial transition (MET) and re-organise into acini-like structures, reminiscent of those formed by epithelial breast cells. We subsequently show, using an inducible CBFβ system, that the MET can be reversed, thus demonstrating the plasticity of RUNX/CBFβ-mediated EMT. Moreover, the MET can be reversed by expression of the EMT transcription factor Slug whose expression is dependent on CBFβ, RUNX1 and RUNX2. Finally, we demonstrate that loss of CBFβ inhibits the ability of metastatic breast cancer cells to invade bone cell cultures and suppresses their ability to form bone metastases in vivo. Together our findings demonstrate that the RUNX/CBFβ complexes can determine the plasticity of the metastatic cancer cell phenotypes, suggesting that their regulation in different micro-environments may play a key role in the establishment of metastatic tumours.

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“…More specifically, interleukin-1 is involved in the development, progression and invasiveness of chemically induced murine fibrosarcomas (7) and the development of asbestosisinduced mesothelioma (8). Blockade of IL-1 has been shown to be able to slow tumor progression in mice and men (9,10).…”

mentioning

confidence: 99%