Editors' ChoiceCancer

With macrophages, tumors won’t go hungry

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Science Translational Medicine  10 Apr 2019:
Vol. 11, Issue 487, eaax1722
DOI: 10.1126/scitranslmed.aax1722

Abstract

Metabolic cross-talk between macrophages and tumor cells results in cancer progression and therapeutic resistance.

Macrophages are immune cells that detect, engulf, and destroy invading microorganisms. During cancer progression, malignant cells hijack macrophages in a process that has not yet been fully explored. In two recent studies, scientists showed that tumor cells induce a maladaptive phenotype in macrophages—known as tumor-associated macrophage (TAMs)—through metabolic rewiring, which can lead to cancer progression and therapeutic resistance.

In the first study, Goossens and colleagues investigated how tumor cells switch macrophages into TAMs. Specifically, they demonstrated that the extracellular matrix component hyaluronic acid released by ovarian cancer cells induces a TAM phenotype by enhancing cholesterol efflux. The authors utilized loss-of-function studies in macrophages to show that the cholesterol efflux transporters ABCA1 and ABCG1 are essential drivers of tumor progression in mouse models.

Why do cancer cells need more TAMs? Some studies suggest that high infiltration of macrophages induces an immunosuppressive niche that protects cancer cells and accelerates their growth. Halbrook et al. addressed this question from a metabolic and therapeutic perspective. Using a metabolomics approach, they identified a range of metabolites, including many pyrimidines, released by TAMs into their culture medium. Because of their structural similarity, they hypothesized that macrophage pyrimidines might diminish the efficacy of gemcitabine, a pyrimidine antinucleoside and chemotherapy agent used to treat patients with pancreatic cancer. Indeed, they found that a higher dose of gemcitabine is required to kill pancreatic cancer cells in a deoxycytidine-dependent manner. By using isotope tracing and metabolic enzyme ablation experiments, the authors showed that gemcitabine resistance depends on de novo pyrimidine biosynthesis in macrophages. Lastly, the authors revealed that macrophage-depleting strategies were efficacious in improving response to gemcitabine in a mouse model of pancreatic cancer.

Cholesterol and pyrimidines biosynthesis are energetically costly. It is worth investigating whether instead of making these compounds, proliferating tumor cells acquire cholesterol and pyrimidines from TAMs as ready-made nutrients. Overall, both publications affirm the therapeutic potential of targeting macrophages in ovarian and/or pancreatic cancers. Future research is warranted to examine whether similar metabolic dependencies exit in other cancer types.

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