IL-1β Blockade Attenuates Thrombosis in a Neutrophil Extracellular Trap-Dependent Breast Cancer Model

Abstract

Cancer patients are at increased risk of developing thrombosis, comorbidity that has been associated with increased neutrophil counts and the formation of neutrophil extracellular traps (NETs). Interleukin-1β (IL-1β) modulates the expression of granulocyte colony-stimulating factor (G-CSF), a cytokine that promotes cancer-associated neutrophilia and NET generation. Herein, we combined a murine breast cancer model with a flow-restriction thrombosis model to evaluate whether the IL-1β blockade could interfere with cancer-associated thrombosis. Mice bearing metastatic 4T1 tumors exhibited high neutrophil counts as well as elevated expression of G-CSF and IL-1β in their tumors. On the other hand, mice bearing non-metastatic 67NR tumors showed no elevation in neutrophil counts and displayed low expression levels of G-CSF and IL-1β in their tumors. 4T1 tumor-bearing mice but not 67NR tumor-bearing mice exhibited a NET-dependent prothrombotic state. Pharmacological blockade of IL-1 receptor (IL-1R) decreased the primary growth of 4T1 tumors and reduced the systemic levels of myeloperoxidase, cell-free DNA (cfDNA) and G-CSF, without interfering with the neutrophil counts. Most remarkably, the blockade of IL-1R abolished the prothrombotic state observed in 4T1 tumor-bearing mice. Overall, our results demonstrate that IL-1β might be a feasible target to attenuate cancer-associated thrombosis, particularly in cancer types that rely on increased G-CSF production and involvement of NET formation.

Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response

“…Data were presented as means ± SEM "second-hit" such as infection or stress. Some studies have indicated that NET-promoting effect is attributed to certain tumor-released cytokines or vesicles [30,31]. However, the pattern of secreted factors is highly distinct among various cancers.…”

Neutrophil Extracellular Traps (NETs) Promote Pro-Metastatic Phenotype in Human Breast Cancer Cells through Epithelial–Mesenchymal Transition

“…Similar antimetastatic effects have been observed in hepatocellular carcinoma and breast cancer models [ 20 , 23 ]. Moreover, the degradation of NETs substantially reduces cancer-associated thrombosis in neutrophilia-related breast and pancreas cancer models [ 26 , 66 ]. Interestingly, we observed that the digestion of NETs with DNase had a minor impact on tumor cell migration as well as in the CXCL8 and MMP9 gene expression ( Figure S4 ).…”

“…Primarily described as an antimicrobial mechanism, NETs are composed of a double-stranded DNA decorated with neutrophil nuclear and granular proteins, such as citrullinated histones, myeloperoxidase, metalloproteinases, and elastase [ 18 ]. Subsequent studies have demonstrated that NETs have several pro-tumoral capabilities, including the ability to sequester circulating tumor cells and contribute to metastasis [ 19 , 20 ], to support primary tumor growth [ 21 , 22 ], to modulate the pro-inflammatory tumor microenvironment [ 23 , 24 ] and to establish the cancer-associated prothrombotic state [ 25 , 26 , 27 ]. It is unclear, however, whether NETs may influence EMT to support tumor progression.…”

Neutrophils: Orchestrators of the Malignant Phenotype

“…Interestingly, it has recently been shown that immature neutrophils preferentially respond to cancer cell derived C3a to promote their migration (31). Subsequently, it was shown that breast cancer cells that expressed high levels of G-CSF and IL-1β exhibited high neutrophil counts and tumor-associated thrombosis, which was dependent on NET formation (32). Pharmacological blockade of IL-1 receptor signaling reduced NET formation, attenuated tumor-associated thrombosis and impaired tumor growth (32).…”

“…Subsequently, it was shown that breast cancer cells that expressed high levels of G-CSF and IL-1β exhibited high neutrophil counts and tumor-associated thrombosis, which was dependent on NET formation (32). Pharmacological blockade of IL-1 receptor signaling reduced NET formation, attenuated tumor-associated thrombosis and impaired tumor growth (32). NETs can also directly influence cancer cell proliferation.…”