Macrophage PPAR[gamma] inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone

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From: eLife(Vol. 5)
Publisher: eLife Science Publications, Ltd.
Document Type: Report
Length: 13,310 words
Lexile Measure: 1430L

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Abstract :

Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPAR[gamma] loss-of-function mutations, but inhibited by PPAR[gamma] agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPAR[gamma] tumor-suppressive functions. Here we report that macrophage PPAR[gamma] deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPAR[gamma] target in macrophage whose expression is enhanced by PPAR[gamma] loss but repressed by PPAR[gamma] activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPAR[gamma] and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPAR[gamma] and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects. DOI: http://dx.doi.org/10.7554/eLife.18501.001 eLife digest The immune system can both contribute to cancer progression and restrain the growth of tumors. Some immune cells -- called macrophages -- create an inflammatory environment around a tumor, which can support the spread of the cancer cells. Independent observations and experiments have shown that a protein called PPAR[gamma] can suppress the development and growth of tumors. Drugs called thiazolidinediones (or TZDs for short), which are normally used to treat type 2 diabetes, activate PPAR[gamma] and therefore have anti-tumor effects. However, it is not fully understood how PPAR[gamma] and TZDs suppress tumor development. Cheng et al. hypothesized that the PPAR[gamma] protein and TZDs can inhibit the activity of the inflammatory macrophages that help tumors to develop. To test this, mice were genetically engineered so that their macrophages could not produce the PPAR[gamma] protein. These engineered mice were more likely to develop breast cancer than normal. Furthermore, the breast tumors in the modified mice did not shrink when they were treated with TZDs, whereas the tumors of normal mice did. Cheng et al. also found that PPAR[gamma] inhibits the ability of macrophages to produce a protein called Gpr132, which itself contributes to inflammation and allows breast cancer cells to grow. Mice that were unable to produce Grp132 displayed less inflammation, and cancer growth was blocked. Drugs that inhibited the activity of Grp132 in normal mice also reduced the ability of breast tumors to spread. Future experiments will need to examine exactly how the Gpr132 proteins produced by macrophages communicate with the cancer cells. Furthermore, developing new drugs that can inhibit Gpr132 could ultimately lead to more effective treatments for cancer. DOI: http://dx.doi.org/10.7554/eLife.18501.002

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Gale Document Number: GALE|A473057208