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Metastatic tumours promote monocyte mobilisation (#198)

Agnieszka Swierczak ¹ , Andrew D Cook ¹ , Christina M Restall ² , Robin L Anderson ² , John A Hamilton ¹

University of Melbourne, Parkville, VIC, Australia
Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Metastasis is the main cause of morbidity and mortality in breast cancer patients. Treatment options remain limited for women presenting with advanced disease in part because of our incomplete understanding of the cellular processes involved in metastasis. The association between inflammation and cancer initiation is well recognised, but the link between inflammation and metastasis is not yet clear. Macrophages are the main immune cell type found in breast tumours. Tumour associated macrophages (TAMs) have been implicated in a number of key steps required for metastasis. The aim of this project is to determine if systemic blood monocyte and/or primary tumour macrophage numbers are associated with tumour growth and metastatic capacity. We utilised three isogenic murine mammary tumour variants, 4T1.2 (highly metastatic), 66cl4 (weakly metastatic) and 67NR (non-metastatic). These cells were inoculated into the mammary glands of Balb/C mice and primary tumour growth monitored. Mice were culled at various times during primary tumour growth and monocyte/macrophage subpopulations in the peripheral blood and primary tumours were assessed by flow cytometry. Ly6C was used as a marker for monocyte subpopulations. We found that Ly6C^lomacrophage numbers were increased in metastatic primary tumours vs. non-metastatic even though no difference was seen in tumour volume or weight. Systemic blood Ly6C^hi (immature) monocyte numbers were also associated with metastatic capacity, but again not with tumour volume or weight. Depletion of Ly6C^lo(mature) monocytes by clodronate liposomes reduced metastasis to lung. A model is proposed in which metastatic tumours promote mobilisation of cells from the bone marrow resulting in infiltration of Ly6C^hi monocytes into the primary tumour, where they mature into Ly6C^lo cells and assist in the process of tumour cell dissemination to distant tissues such as the lung.