암세포의 호기성 당분해에서 종양 침윤 대식세포의 역할 규명 연구

Abstract

Tumor microenvironment consists of various cell types and conditions promoting tumor growth and malignancy. Tumor-associated macrophages (TAM), the major population of infiltrated immune cells, have been received much attention as therapeutic targets due to their protumoral role producing growth factors and proteases thereby promoting tumor progression. Cancer cells reprogram their metabolic patterns towards taking up much more glucose and processing it through aerobic glycolysis for their survival in limited nutrients. Several intracellular oncogenic pathways have been studied for regulating aerobic glycolysis whereas the relationship between TAM and tumor metabolism has not been revealed. In this study, we investigated the role of TAM in aerobic glycolysis in tumors. We used subcutaneous mouse tumor model with Lewis lung carcinoma (LLC) cell line and depleted TAM by clodronate liposome (Clod) treatment, a liposomal drug causing apoptosis of macrophages. By performing positron emission tomography (PET) imaging, we observed that depletion of TAM lead to significantly decreased 18fluorodeoxyglucose (FDG) uptake in LLC tumors. To determine functional changes in tumor cells, we designated Hoechst 33342birghtKeratin-19+ populations as aerobic tumor cells and isolated them from Clod-treated tumor-bearing mice. We found that TAM depletion by Clod changed the metabolic function of tumor cells from glycolysis to oxidative phosphorylation (OXPHOS), indicating the role of TAM in promoting tumor glycolysis. To investigate the mechanism how TAM facilitate tumor glycolysis, we analyzed the supernatant from bone marrow-derived macrophages (BMDM) co-cultured with LLC cancer cells. Among the secreted factors from BMDM, we observed that it was tumor necrosis factor-α (TNF-α) that promotes glucose uptake and increases glycolytic enzyme expressions in cancer cells. TNF-α was indeed expressed from TAM in the LLC tumors. We further proved the effect of TNF-α in tumor glycolysis by using Enbrel, a clinically available blockade of TNF-α, significantly inhibiting glucose uptake in mouse tumors to the level comparable to Clod. In conclusion, these results demonstrate that TAM are novel contributors to enhance aerobic glycolysis in tumors, indicating that therapeutic responses targeting tumor metabolism could be predicted by monitoring TAM infiltration.