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.