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Review
. 2021 Sep 9;21(1):479.
doi: 10.1186/s12935-021-02121-5.

Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells

Xiao Li  1 , Hongming Zhu  2 , Weixuan Sun  1 , Xingru Yang  3 , Qing Nie  1 , Xuedong Fang  4
Affiliations
Review

Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells

Xiao Li et al. Cancer Cell Int. .

Abstract

Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, play an indispensable role in cancer initiation, progression, metastasis, and metabolism. The limitations of traditional treatments can be partly attributed to the lack of understanding of the role of the tumor stroma. For this reason, CAF targeting is gradually gaining attention, and many studies are trying to overcome the limitations of tumor treatment with CAF as a breakthrough. Glutamine (GLN) has been called a "nitrogen reservoir" for cancer cells because of its role in supporting anabolic processes such as fuel proliferation and nucleotide synthesis, but ammonia is a byproduct of the metabolism of GLN and other nitrogenous compounds. Moreover, in some studies, GLN has been reported as a fundamental nitrogen source that can support tumor biomass. In this review, we discuss the latest findings on the role of GLN and ammonia in the crosstalk between CAFs and cancer cells as well as the potential therapeutic implications of nitrogen metabolism.

Keywords: Ammonia; Cancer cells; Cancer-associated fibroblasts; Glutamine; Tumor microenvironment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Origins and functions of CAFs. The main origin of CAFs include epithelial cells, mesenchymal stem cells, mesothelial cells, normal fibroblasts, cancer cells, adipocytes and so on. The influence of CAFs on tumor cells includes various aspects like drug resistance, tumor proliferation, metastasis, invasion, migration, immunomodulation, and angiogenesis
Fig. 2
Fig. 2
Glutamine metabolism between CAFs and cancer cells. CAFs can provide cancer cells with Lac, Gln and other nutrients into TCA cycle and urea cycle, and then promote the growth and development of tumor cells.The black pointed arrow heads indicate material transportation. The blue blunt arrowheads indicate inhibitory interactions. Arg ariginine, α-KG α-Ketoglutaric acid, Cit citrate, Lac lactose, Glc glucose, Glu glutamate, GSH glutathione, Orn ornithine, PYR pyruvate
Fig. 3
Fig. 3
Oncogenic regulation of GLN metabolism. Driven by oncogenes and ammonia concentration, CAFs can secrete nutrients such as Glu and cytokines, thus promoting the metabolic changes of tumor cells and the growth and development of cancer cells. The red pointed arrow heads indicate activation interactions. The black pointed arrow heads indicate material transportation. The blue blunt arrowheads indicate inhibitory interactions
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