Transiently Entrapped Circulating Tumor Cells Interact with Neutrophils to Facilitate Lung Metastasis Development

Abstract

It is unknown why only a minority of circulating tumor cells trapped in lung capillaries form metastases and involvement of immune cells remains uncertain. A novel model has been developed in this study showing that neutrophils regulate lung metastasis development through physical interaction and anchoring of circulating tumor cells to endothelium. Human melanoma cells were i.v. injected into nude mice leading to the entrapment of many cancer cells; however, 24 hours later, very few remained in the lungs. In contrast, injection of human neutrophils an hour after tumor cell injection increased cancer cell retention by ∼3-fold. Entrapped melanoma cells produced and secreted high levels of a cytokine called interleukin-8 (IL-8), attracting neutrophils and increasing tethering β 2 integrin expression by 75% to 100%. Intercellular adhesion molecule-1 on melanoma cells and β 2 integrin on neutrophils interacted, promoting anchoring to vascular endothelium. Decreasing IL-8 secretion from melanoma cells lowered extracellular levels by 20% to 50%, decreased β 2 integrin on neutrophils by ∼50%, and reduced neutrophil-mediated extravasation by 25% to 60%, resulting in ∼50% fewer melanoma cells being tethered to endothelium and retained in lungs. Thus, transendothelial migration and lung metastasis development decreased by ∼50%, showing that targeting IL-8 in melanoma cells has the potential to decrease metastasis development by disrupting interaction with neutrophils.

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

“…6c,d). An increased number of Gr1 þ cells has been correlated previously with enhanced metastasis [27][28][29] . In parallel we noted a decrease in infiltration of CD4 þ and CD8 þ T cells at early time points after tumour cell injection ( Supplementary Fig.…”

“…Their expansion at metastatic sites generates an immunosuppressive niche that suppresses T cell activation, proliferation and cytotoxicity and also suppresses NK cell cytotoxicity [23][24][25][26] . These cells have been shown to facilitate tumour cell seeding and colonization at metastatic sites and are thereby thought to drive metastasis [27][28][29] .…”

Neutrophils in cancer: neutral no more

“…Enhanced retention of human melanoma cells in lungs can be seen as early as 24 hours after co-injection with neutrophils into nude mice 143 . In experimental lung or liver metastasis models where cancer cell lines are injected into the circulation or spleen, respectively, systemic depletion of neutrophils (via anti-Gr1 antibodies) reduces the formation of metastases 144,145 .…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Neutrophils were also shown to be important for entrapping circulating melanoma cells and thus facilitating lung metastasis development [294]. Melanoma-secreted IL-8 not only attracts neutrophils, but also strongly upregulates β2 integrins, which interact with ICAM-1 on melanoma cells, thereby promoting the anchoring of the tumor cells to vascular endothelium [294].…”

“…Neutrophils were also shown to be important for entrapping circulating melanoma cells and thus facilitating lung metastasis development [294]. Melanoma-secreted IL-8 not only attracts neutrophils, but also strongly upregulates β2 integrins, which interact with ICAM-1 on melanoma cells, thereby promoting the anchoring of the tumor cells to vascular endothelium [294]. Other studies further show that IL-8 increases neutrophil β2 integrin expression with simultaneous shedding of L-selectin (CD62L), thereby promoting their sequestration in the lung [295].…”