Gemcitabine treatment modulates myelopoiesis progenitors and monocytes to promote lung metastasis

Abstract

Abstract Metastasis-associated macrophages (MAMs) play important roles in tumor metastasis through the formation of a pre-metastatic niche. In mouse models of lung metastasis, interstitial macrophages (IMs) markedly accumulate in the lungs and differentiate into MAMs. Regarding the origin of IMs/MAMs, tissue-resident macrophages and bone marrow (BM)-derived classical monocytes (BM-Mo) contribute to the pool of MAMs. Chemotherapy offers long-term clinical benefits to many cancer patients. However, several pre-clinical studies have demonstrated that certain cytotoxic drugs enhance metastasis by multiple mechanisms. Our recent studies suggest that Gemcitabine (GEM) promotes the immunosuppressive function of monocytic MDSC (M-MDSC) in the tumor microenvironment via the tumor-derived GM-CSF and efferocytosis signaling. In this study, we hypothesize that host responses to GEM treatment enhance the accumulation of BM-derived monocytes in lung, which promotes lung metastasis. Multi-dose of GEM treatment induces the increase of BM LSK cells and multipotent progenitors (MPPs) in tumor-free mice, which is associated with the increase of treatment induce mitochondrial ROS (mtROS). Thus, the percentage of BM Ly6C+ monocytes is significantly increased because of increased progenitor monocyte differentiation potential and monocyte proliferation. Further, GEM treatment increases the percentages of lung CCR2+Ly6C+ monocytes and IMs. Consequently, GEM pre-treated mice have a significantly higher number of pulmonary metastases compared to untreated mice in the experimental metastasis model. These results suggest a novel mechanism for chemotherapy induced metastasis via the modulation of myelopoiesis progenitors.