Chemotherapy may facilitate colorectal cancer metastasis through vessel formation by upregulating G-CSF

Abstract Background Chemotherapy remains the mainstay of treatment for various cancers. However recent studies suggested that it may also induce local or systemic changes that promote the dissemination and proliferation of cancer cells leading to successful metastasis. Understanding this process is therefore instrumental to help us identify patient population that may or may not be benefit from chemotherapy, and develop innovative approaches to prevent metastasis. Methods In this study, we investigated the mechanism of chemotherapy causing the metastasis of colorectal cancer, and the roles of G-CSF induced by chemotherapy in the vessel formation. Eight-week-old C57/BL6 mice were used as animal models in this study to investigate the lung metastasis by the chemotherapy. Conditional endothelial cell STAT3−/− (Signal Transducer and Activator of Transcription, STAT) knockout mice (STAT3flox/flox; Tek-Cre mice), were used to investigate the function of STAT3 on lung metastasis under the chemotherapy. Bone marrow and plasma was selected to detect the mobilization of endothelial progenitor cells (EPCs) and MDSCs. To trace BM-derived cells, we prepared chimeric mouse transplanted with BM cells from green fluorescent protein (GFP) transgenic mouse. In vitro, experiments were performed in human umbilical vein endothelial cells (HUVEC) to analyse the function of G-CSF on angiogenesis. Detected the G-CSF content in the plasma of the patients who received an adjuvant chemotherapy with the XELOX (oxaliplatin plus capecitabine) regimen. Results Our study showed that oxaliplatin chemotherapy could increase the expression of G-CSF to promote lung metastasis. First, G-CSF/STAT3 signaling facilitated lung metastasis by enhancing vascular adhesion rather than diminishing the blood vessel density. G-CSF also promoted Endothelial Progenitor Cells (EPCs) mobilization that devoted to vasculogenesis, a critical step for vessel density in metastatic sites; moreover, chemotherapy augmented the mobilization of MDSCs from the bone marrow by G-CSF. In consistent with these, anti-G-CSF suppressed the formation of a functional vasculature and induced tumoral immunosuppression, resulting in an anti-metastasis effect during chemotherapy. Furthermore, at human level, we observed high level of G-CSF, either at baseline or after receiving adjuvant XELOX chemotherapy, correlated with poor overall and recurrence-free survival. Conclusions These results demonstrate that certain chemotherapy could paradoxically result in worse outcome due to increased expression of G-CSF. Our findings provide mechanistic insight into cautious use of G-CSF and potential utility of anti-G-CSF in personalized cancer therapy.