Macrophages are exploited from an innate wound healing response to facilitate cancer metastasis

Muliaditan, Tamara and Caron, Jonathan and Okesola, Mary and Opzoomer, James W. and Kosti, Paris and Georgouli, Mirella and Gordon, Peter and Lall, Sharanpreet and Kuzeva, Desislava M. and Pedro, Luisa and Shields, Jacqueline D. and Gillett, Cheryl E. and Diebold, Sandra S. and Sanz-Moreno, Victoria and Ng, Tony and Hoste, Esther and Arnold, James N. (2018) Macrophages are exploited from an innate wound healing response to facilitate cancer metastasis. Nature Communications, 9 (1). 2951. ISSN 2041-1723 (https://doi.org/10.1038/s41467-018-05346-7)

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Abstract

Tumour-associated macrophages (TAMs) play an important role in tumour progression, which is facilitated by their ability to respond to environmental cues. Here we report, using murine models of breast cancer, that TAMs expressing fibroblast activation protein alpha (FAP) and haem oxygenase-1 (HO-1), which are also found in human breast cancer, represent a macrophage phenotype similar to that observed during the wound healing response. Importantly, the expression of a wound-like cytokine response within the tumour is clinically associated with poor prognosis in a variety of cancers. We show that co-expression of FAP and HO-1 in macrophages results from an innate early regenerative response driven by IL-6, which both directly regulates HO-1 expression and licenses FAP expression in a skin-like collagen-rich environment. We show that tumours can exploit this response to facilitate transendothelial migration and metastatic spread of the disease, which can be pharmacologically targeted using a clinically relevant HO-1 inhibitor.

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