Hypoxia is a common feature and poor prognostic factor in many solid cancers including breast cancer. Within the primary tumour, hypoxia acts as a strong selective pressure that promotes angiogenesis, invasion and metastatic spread of tumour cells. The pro-tumourigenic properties of future metastatic sites are determined by the interactions between factors secreted by the primary tumour and bone marrow-derived cell lineages, which drives formation of pre-metastatic niches in distant organs before the arrival of tumour cells. Individually, various hypoxic tumour-derived factors have been associated with pre-metastatic niche formation, which suggests hypoxia may be the unifying process crucial in creating these permissive microenvironments for disseminating tumour cells.
Here, we demonstrate in different immune competent, syngeneic orthotopic breast cancer models, that primary tumour hypoxia promotes pre-metastatic niche formation. Cell-free supernatant derived from hypoxic breast tumour cells results in increased bone marrow-derived cell infiltration into the lungs in the absence of a primary tumour, and leads to increased metastatic burden in breast and melanoma experimental metastasis models.
We furthermore define bone marrow-derived CD11b+/Ly6Cmed/Ly6G+ and CD3-/NK1.1+ NK cell lineages as main constituents of the pre-metastatic niche, and show that NK cell cytotoxicity and maturity is decreased. This subset of myeloid cells suppresses NK cell function to create an immune-suppressed environment allowing for increased tumour cell expansion and metastatic growth. Additionally, secretion of the systemic soluble factor MCP-1/CCL2 by hypoxic breast cancer cells, controls myeloid cell mobilisation and recruitment to the pre-metastatic niche. This data demonstrates a pivotal role for factors produced by hypoxic primary tumour cells in orchestrating the recruitment and modulation of bone marrow-derived cells in the pre-metastatic niche in breast cancer.