Reactive myelopoiesis and FX-expressing macrophages triggered by chemotherapy promote cancer lung metastasis
Caijun Wu, Qian Zhong, Rejeena Shrestha, Jingzhi Wang, Xiaoling Hu, Hong Li, Eric C. Rouchka, Jun Yan, Chuanlin Ding
Caijun Wu, Qian Zhong, Rejeena Shrestha, Jingzhi Wang, Xiaoling Hu, Hong Li, Eric C. Rouchka, Jun Yan, Chuanlin Ding
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Research Article Immunology

Reactive myelopoiesis and FX-expressing macrophages triggered by chemotherapy promote cancer lung metastasis

Abstract

Several preclinical studies have demonstrated that certain cytotoxic drugs enhance metastasis, but the importance of host responses triggered by chemotherapy in regulating cancer metastasis has not been fully explored. Here, we showed that multidose gemcitabine (GEM) treatment promoted breast cancer lung metastasis in a transgenic spontaneous breast cancer model. GEM treatment significantly increased accumulation of CCR2+ macrophages and monocytes in the lungs of tumor-bearing as well as tumor-free mice. These changes were largely caused by chemotherapy-induced reactive myelopoiesis biased toward monocyte development. Mechanistically, enhanced production of mitochondrial ROS was observed in GEM-treated BM Lin−Sca1+c-Kit+ cells and monocytes. Treatment with the mitochondria targeted antioxidant abrogated GEM-induced hyperdifferentiation of BM progenitors. In addition, GEM treatment induced upregulation of host cell–derived CCL2, and knockout of CCR2 signaling abrogated the pro-metastatic host response induced by chemotherapy. Furthermore, chemotherapy treatment resulted in the upregulation of coagulation factor X (FX) in lung interstitial macrophages. Targeting activated FX (FXa) using FXa inhibitor or F10 gene knockdown reduced the pro-metastatic effect of chemotherapy. Together, these studies suggest a potentially novel mechanism for chemotherapy-induced metastasis via the host response–induced accumulation of monocytes/macrophages and interplay between coagulation and inflammation in the lungs.

Authors

Caijun Wu, Qian Zhong, Rejeena Shrestha, Jingzhi Wang, Xiaoling Hu, Hong Li, Eric C. Rouchka, Jun Yan, Chuanlin Ding

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Figure 7

PTX or combination of PTX and DOX treatment elicits host responses like GEM.

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PTX or combination of PTX and DOX treatment elicits host responses like ...
B6 WT mice were treated PTX (10 mg/kg, IP) or combination of PTX and DOX (2 mg/kg) or Cremophor EL control 3 times in 2 weeks. Lungs and BM were collected 2 days later after last treatment. (A) Percentages of BM Ly6C+ monocytes, LSK cells, and MPPs in BM of treated and control mice (n = 5). (B) Total cell numbers of lung Ly6C+ monocytes (n = 5–7). (C) Total cell numbers of lung macrophages (CD11bhiF4/80+CD11c−) (n = 5–7). (D) qRT-PCR for F10 gene in lung macrophages from treated and control mice (n = 4–5). (E) B6 WT mice were treated with PTX or combination of PTX and DOX or Cremophor EL control along with rivaroxaban or solvent control (mock) for 2 weeks. E0771-GFP cells (4 × 105) were intravenously injected into these mice 2 days later after last treatment. The percentage of GFP+ tumor cells in the lung tissues was determined 2 weeks later (n = 5–6). (F and G) Lung cells were stimulated with PMA/ionomycin (MilliporeSigma) in the presence of Brefeldin A (BioLegend) for 4–6 hours, then permeabilized for surface and intracellular staining. tSNE analysis of CyTOF immunophenotyping of the lungs from mice treated with PTX, PTX plus DOX, or solvent control (n = 4–5). All samples combined (F), combined samples from each group (G, top), and frequencies in different groups (G, bottom). Cell population 13 (red) is TNF-α–producing CCR2+ macrophages. Data are representative of 2 independent experiments and presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by ordinary 1-way ANOVA (A, B, D, E, and G).