Reactive myelopoiesis and FX-expressing monocyte-derived macrophages triggered by chemotherapy promotes cancer lung metastasis

Abstract

Abstract Lung metastasis-associated macrophages (MAMs) play a very important role in tumor metastasis. In mouse models of lung metastasis, interstitial macrophages (IMs) markedly accumulate and differentiate into MAMs. Several pre-clinical studies have demonstrated that certain cytotoxic drugs enhance metastasis. In this study, we hypothesize that host responses to chemotherapy treatment enhance breast cancer metastasis by modulation of lung macrophage toward a pro-metastatic phenotype. Here, we show that multi-dose chemo treatment promotes breast cancer lung metastasis in the spontaneous breast cancer animal model. Pretreatment with Gemcitabine and Paclitaxel induces a significantly higher number of pulmonary metastases in the experimental metastasis model. Mechanistically, multi-dose of chemotherapy induces reactive myelopoiesis characterized by increase of BM LSK cells and multipotent progenitors in tumor-free mice, which is associated with the increase of mitochondrial ROS. Further, chemokine CCL2 expression is significantly increased in the plasma and lung tissues of chemo-treated tumor-free mice. Consequently, the percentage of BM Ly6C+ monocytes are significantly increased because of increased progenitor monocyte differentiation potential and monocyte proliferation, which results in an increase of lung monocytes and IMs with enhanced expression of coagulation factor X (FX). Inhibition of activated FX (FXa) can inhibit chemotherapy-induced lung metastasis. Together, these studies suggest a novel mechanism for chemotherapy induced metastasis via the modulation of BM-derived monocytes/macrophages and extravascular clotting in lung tissues. Supported by grants from NIH (P20GM135004)