Hyperglycolysis-Inflammation Connect as a Mechanistic Hot Spot in Oxidatively Compromised Cancer

Abstract

Hyperglycolysis, as a major bioenergetics shift in the growing tumor cells, ensures adequate amount of ATP synthesis by avoiding mitochondrial oxidative mechanism and thereby protects tumor cells from reactive oxygen species (ROS)-induced cellular damage. Such an oxidatively compromised state of the tumor cells is considered crucial for making them immortal. The generation of pro-inflammatory factors around the tumor cells is advocated as another important event, and that, together with the hyperglycolysis, it constitutes a pro-tumorigenic tumor microenvironment (TME) and facilitates in vivo tumorigenesis. Herein, the enhanced lactate secretion, due to upregulated aerobic glycolysis, by the tumor stem cells (TSCs), acts as a key integrator of hyperglycolysis-inflammation connect. Consequently, dynamic interaction takes place between the TSC, the tumor-associated macrophages (TAMs), and the tumor matrix around the TSC niche. The TAMs play a central role in orchestrating neoplastic growth around the TSCs. The lactate-dependent transition from M1 (tumoricidal) macrophages to M2 (immunosuppressive and pro-tumorigenic) phenotype is considered the most critical event of this mechanism. In this chapter, we have attempted to summarize the recent advances in the area of tumor growth associated with hyperglycolysis-inflammation connect in general and on the TAM-mediated endothelial-mesenchymal transition (EMT), required for angiogenesis and metastasis in the growing in vivo tumors in particular. The key hyperglycolytic players focused are hexokinase II, inducible phosphofructokinase 2, pyruvate kinase M2, and M4-lactate dehydrogenase, and those of inflammation are colony-stimulating factor 1 (CSF1) and several other cytokines. The TAM, the programmed cell death-1 ligand (PD-L1), and PD-1-mediated suppression of T cell response against cancer cells have been given special focus. Similarly, the role of REDD1 (regulated in development and DNA damage responses 1), a potent stress response factor, in TAM-mediated metastasis and neovascularization, has been advocated as an evolving concept of TAM-mediated tumorigenesis. In view of the above, we have tried to summarize the current status about whether these key players of hyperglycolysis-inflammation axis could be exploited as targets for restricting tumor growth in vivo. © Springer Nature Singapore Pte Ltd. 2022.