Comprehensive Proteomics Analysis Reveals Metabolic Reprogramming of Tumor-Associated Macrophages Stimulated by the Tumor Microenvironment.
Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment. Although a role for TAMs in promoting tumor progression has been revealed, the differentiation mechanisms and intrinsic signals of TAMs regulated by the tumor microenvironment remain unclear. Here we constructed an in vitro TAMs cell model, TES-TAMs, which is from tumor-extract-stimulated bone-marrow-derived macrophages. We performed a comparative proteomics analysis of bone-marrow-derived macrophages and TES-TAMs, which indicated that TES-TAMs possessed characteristic molecular expression of TAMs. Intriguingly, the signal pathways enriched in up-regulated differentially expressed proteins of TAMs demonstrated that glycolysis metabolism reprogramming may play an important role in TAM differentiation. We found that hexokinase-2, a key mediator of aerobic glycolysis, and the downstream proteins PFKL and ENO1 were remarkably increased in both TES-TAMs and primary TAMs from our MMTV-PyMT mice model. This phenomenon was then verified in human THP-1 cell lines stimulated by tumor extract solution from breast cancer patient. Taken together, our study provides insight into the induction of TAM differentiation by the tumor microenvironment through metabolic reprogramming.
School of Life Sciences, Tsinghua University , Beijing 100084, P. R. China.|State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine , Beijing 102206, P. R. China.
Di
D
Liu
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine , Beijing 102206, P. R. China.
Cheng
C
Chang
Department of Orthopedics, PLA General Hospital , Beijing 100853, P. R. China.
Ning
N
Lu
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine , Beijing 102206, P. R. China.
Xing
X
Wang
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine , Beijing 102206, P. R. China.|Department of Biochemistry and Molecular Biology, Anhui Medical University , Hefei, Anhui Province 230032, P. R. China.
Qian
Q
Lu
Department of Orthopedics, PLA General Hospital , Beijing 100853, P. R. China.
Xiaojie
X
Ren
Department of Orthopedics, PLA General Hospital , Beijing 100853, P. R. China.
Peng
P
Ren
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine , Beijing 102206, P. R. China.
Dianyuan
D
Zhao
Vascular Biology Research Institute, Guangdong Pharmaceutical University , Guangzhou, Guangdong Province 510006, P. R. China.
Lijing
L
Wang
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine , Beijing 102206, P. R. China.
Yunping
Y
Zhu
School of Life Sciences, Tsinghua University , Beijing 100084, P. R. China.|State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine , Beijing 102206, P. R. China.
Fuchu
F
He
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine , Beijing 102206, P. R. China.|Department of Biochemistry and Molecular Biology, Anhui Medical University , Hefei, Anhui Province 230032, P. R. China.
Li
L
Tang
D000818:Animals; D002454:Cell Differentiation; D065150:Cellular Reprogramming / Q000187:drug effects*; D045424:Complex Mixtures / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000235:genetics*
D045424:Complex Mixtures; D016207:Cytokines; D020543:Proteome; D006593:Hexokinase
proteomics; tumor microenvironment; tumor-associated macrophages