Hyperglycemia Impairs Neutrophil Mobilization Leading to Enhanced Metastatic Seeding

Preexisting diabetes is a risk factor for the development of multiple types of cancer. Additionally, diabetic patients face a poorer prognosis when diagnosed with cancer. To gain insight into the effects of hyperglycemia, a hallmark of diabetes, on tumor growth and metastatic progression, we combined mouse models of cancer and hyperglycemia. We show that while hyperglycemia attenuates primary tumor growth, it concomitantly increases metastatic seeding in a distant organ. We further show that the increase in metastatic seeding is due to impaired secretion of granulocyte colony-stimulating factor (G-CSF) and impaired neutrophil mobilization. Normalizing blood glucose levels using insulin rescues neutrophil recruitment and tumor growth and concomitantly reduces metastatic seeding. These results provide links among hyperglycemia-induced changes in neutrophil mobilization, primary tumor growth, and metastatic progression. Furthermore, our observations highlight the importance of normalizing blood glucose levels in hyperglycemic cancer patients. Underlying diabetes is a poor prognostic factor for cancer patients. Fainsod-Levi et al. demonstrate that underlying hyperglycemia increases metastatic spread. Hyperglycemia impairs G-CSF secretion, thereby hindering the mobilization of antitumor neutrophils. Poor neutrophil mobilization in hyperglycemia leads to increased survival of disseminated tumor cells and consequently increasing the metastatic burden.