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 4

Upregulation of mtROS in BM microenvironment triggered by GEM treatment.

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Upregulation of mtROS in BM microenvironment triggered by GEM treatment....
Naive tumor-free C57BL/6 mice were treated with 4 doses of GEM (60 mg/kg, IP). BM was harvested 2 days later after the last treatment. (A and B) mtROS production in LSK cells (A) and BM monocytes (B) was determined by using MitoSOX dye (5 μM) (n = 3–5). (C) Mitochondria potential was determined by using TMRM dye (500 nM) followed by lineage marker and Sca1 and c-Kit antibody staining. The percentages of TMRMhi and TMRMlo LSK cells were summarized (n = 3–4). (D) BM cells were stained with MitoTracker Green and MitoTracker Red followed by BM LSK cell markers. Representative plots gated on LSK cells and summarized functional and dysfunctional mitochondria were shown (n = 4). (E) BM cells (1 × 106) from PBS- and GEM-pretreated mice were treated with MitoTEMPO (10 μM) and cultured in the presence of GM-CSF (20 ng/mL) for 2 days. The culture medium including nonadherent cells was entirely discarded at day 3 and replaced by medium containing GM-CSF and MitoTEMPO for an additional 4 days. Cell numbers of CD11b+Ly6C+ monocytes after 6 days’ culture was determined by cell counting and flow cytometry (n = 3). Data are representative of 2 experiments and presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by ordinary 1-way ANOVA (C–E) or unpaired 2-sided t test (A and B).