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
View: Text | PDF
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

×

Figure 5

Chemotherapy-induced upregulation of macrophage-synthesized FX contributes to lung metastasis.

Options: View larger image (or click on image) Download as PowerPoint
Chemotherapy-induced upregulation of macrophage-synthesized FX contribut...
(A) RNA-Seq analysis in lung macrophages sorted from naive mice after GEM and PBS treatment (n = 3). Volcano plot for differential gene expression in lung macrophages from GEM-treated mice as compared with PBS-treated mice. (B) Top 20 enriched GO biological processes for the genes in lung macrophages from GEM-treated mice as compared with PBS-treated mice. (C) qRT-PCR for F10 gene in lung macrophages from GEM- and PBS-treated mice. (D) Levels of total FX and FXa in the plasma of GEM- and PBS-treated mice (n = 10–12). (E) Naive mice were treated with GEM and rivaroxaban, or solvent control, followed by IV injection of 4 × 105 E0771-GFP cells. The lung tumor burden was examined by measuring GFP+ tumor cells within lung CD45– cells 14 days after tumor cell injection (n = 5). (F) Mice were treated with GEM and rivaroxaban, or solvent control, followed by IV injection of 1 × 105 E0771-GFP cells. Lung macrophages were depleted by IV injection of clodrosome during the GEM/rivaroxaban treatment and tumor development. The lung tumor burden was examined by measuring GFP+ tumor cells within lung CD45– cells 14 days after tumor cell injection (n = 5). (G) Experimental scheme for adoptive transfer of E0771 CM–stimulated (24 hours) control and F10 gene–knockdown macrophages (2 × 106/mouse) and E0771-GFP (4 × 105/mouse) injection. (H) The lung tumor burden was examined by measuring GFP+ tumor cells within lung CD45– cells 17 days after tumor cell injection (n = 10–12). The data in H represent a combination of 2 experiments. Each dot represents 1 mouse. *P < 0.05, **P < 0.01, and ***P < 0.001 by unpaired 2-sided t test (C, D, E, and H) or ordinary 1-way ANOVA (F).