Editors' ChoiceCancer

Maestro macrophages conduct a widely disseminated symphony

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Science Translational Medicine  24 Jan 2018:
Vol. 10, Issue 425, eaar7521
DOI: 10.1126/scitranslmed.aar7521

Abstract

Macrophages break down tissue junctions and allow for breast cancer dissemination and metastasis.

When enjoying a symphony, the eye is often drawn to the silent conductor. Without a conductor, the instruments fail to coordinate and disseminate in melody throughout the concert hall. Similarly, in their recent paper, Linde and colleagues demonstrate that macrophages serve as the conductors that coordinate breast cancer dissemination and metastasis; macrophage instruction transforms cancer cells from individual instruments to a powerful and deadly symphony. Specifically, the authors use a mouse model of HER2+ breast cancer to study the influence of macrophages on dissemination of a specific subpopulation of early cancer cells. They demonstrate that cancer cell–secreted chemokine (C-C motif) ligand 2 (CCL2) attracts macrophages, which then secrete Wingless-related integration site 1 (Wnt-1) ligand, resulting in decreased E-cadherin junctions. The authors target the colony-stimulating factor 1 (CSF1R) receptor with an antibody to specifically deplete tissue resident macrophages and prove that this depletion mitigates tumor mass formation and decreases early circulating cancer cells. Concurrently, they demonstrate that macrophage-depleted tumor lesions have increased expression of E-cadherin mRNA and junctions in epithelial cells. Though Wnt1 is known to induce epithelial to mesenchymal transition, here they identify the role of Wnt-1 in coordinating E-cadherin junctions. They next assess late tumor metastasis by blocking CSF1R during the early asymptomatic stages of cancer and demonstrate a decreased number of metachronous metastases per mouse, leading them to conclude that macrophages aid early dissemination of HER2+ cancer cells and subsequent metastasis. These findings were then translated to human Ductal carcinoma in situ (DCIS) lesions where they identified intraepithelial macrophages and a loss of E-cadherin. In summary, the authors describe a well-coordinated symphony conducted by the macrophages where they are attracted to the epithelium of early lesions from cancer cell–secreted CCL2 and create a microenvironment conducive to cancer dissemination and metastasis. Although macrophages have long been known to play a central role in the tumor microenvironment, this study characterizes how macrophages conduct cancer cell dissemination and metastasis. Macrophages might serve as a potential therapeutic target as removing the conductor could revert the powerful symphony back to a weak cacophony of individual instruments.

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