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 3

GEM treatment induces reactive myelopoiesis in tumor-free and tumor-bearing mice with enhanced myeloid potential.

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GEM treatment induces reactive myelopoiesis in tumor-free and tumor-bear...
Naive C57BL/6 and E0771 tumor–bearing mice were treated with 4 doses of GEM (60 mg/kg, IP). BM was harvested 2 days later after last treatment. (A) Representative FACS plots gated on lineage-negative cells and summarized data of LSK cells (Lin–Sca1+c-Kit+) (n = 5–8). (B) Representative FACS plots gated on LSK cells and summarized data of MPPs (CD150–CD48+) (n = 5–8). (C) Representative CFU-GM and CFU-M after 7 days’ culture of BM cells from GEM-treated tumor-free mice in MethoCult GF M3534 methylcellulose-based medium. Numbers of CFU-GM and CFU-M were summarized (n = 4–5). Scale bar, 500 μm. (D) BM cells (1 × 106) were cultured in the presence of 20% E0771-conditioned medium (CM) for 2 days. The culture medium including nonadherent cells was entirely discarded at day 3 and replaced by medium containing E0771 CM for an additional 4 days. The yield of myeloid cells was counted after 6 days’ culture (n = 3). (E) Representative FACS plots of Ly6G–Ly6C+ in vitro–expanded cells. (F) Sorted Ly6G–Ly6C+ cells were cultured with CFSE-labeled OT-I splenocytes in the presence of OVA (20 μg/mL) for 3 days. T cell proliferation was measured by flow cytometry (n = 3). Data are representative of 2 or 3 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, and F) or unpaired 2-sided t test (C and D).