Neutrophils Promote Liver Metastasis via Mac-1–Mediated Interactions with Circulating Tumor Cells

Abstract

Although circulating neutrophils are associated with distant metastasis and poor outcome in a number of epithelial malignancies, it remains unclear whether neutrophils play an active causal role in the metastatic cascade. Using in vivo models of metastasis, we found that neutrophils promote cancer cell adhesion within liver sinusoids and, thereby, influence metastasis. Neutrophil depletion before cancer cell inoculation resulted in a decreased number of gross metastases in an intrasplenic model of liver metastasis. This effect was reversed when inflamed neutrophils were co-inoculated with cancer cells. In addition, early adhesion within liver sinusoids was inhibited in the absence of neutrophils and partially restored with a short perfusion of isolated activated neutrophils. Intravital microscopy showed that cancer cells adhered directly on top of arrested neutrophils, indicating that neutrophils may act as a bridge to facilitate interactions between cancer cells and the liver parenchyma. The adhesion of lipopolysaccharide-activated neutrophils to cancer cells was mediated by neutrophil Mac-1/ICAM-1. Our findings, therefore, show a novel role for neutrophils in the early adhesive steps of liver metastasis. Cancer Res; 72(16);

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…This effect was reversed when inflamed neutrophils were co-inoculated with tumor cells [307]. H-59 cells showed reduced adhesion to liver sinusoids of CD11b deficient mice [307]. In contrast, our own work, using mouse models of breast cancer, shows that neutrophils are stimulated by tumor-secreted factors and acquire an anti-tumor phenotype [32].…”

“…Neutrophil depletion prior to cancer cell inoculation reduced the number of liver metastases [307]. This effect was reversed when inflamed neutrophils were co-inoculated with tumor cells [307]. H-59 cells showed reduced adhesion to liver sinusoids of CD11b deficient mice [307].…”

“…Neutrophils were also shown to promote liver metastasis of Lewis lung carcinoma (H-59 subline) cells through Mac1 (CD11b/ CD18)-mediated interaction with circulating tumor cells [307]. Neutrophil depletion prior to cancer cell inoculation reduced the number of liver metastases [307].…”

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 . Intravital imaging has shown that cancer cells colocalize with endothelial cell-associated neutrophils in a CD11b-dependent manner 144 , suggesting that neutrophils guide cancer cells into tissues and/or retain them there rather than supporting the outgrowth of secondary tumors.…”

“…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 . Intravital imaging has shown that cancer cells colocalize with endothelial cell-associated neutrophils in a CD11b-dependent manner 144 , suggesting that neutrophils guide cancer cells into tissues and/or retain them there rather than supporting the outgrowth of secondary tumors. Neutrophils use neutrophil extracellular traps (NETs) for this purpose to sequester circulating cancer cells in a mesh of nucleic acids, antimicrobial factors and enzymes, and to promote adhesion at distant organ sites 146 .…”