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Inflammation and Metabolism in Cancer Cell-Mitochondria Key Player

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Review

Inflammation and Metabolism in Cancer Cell-Mitochondria Key Player

Monica Neagu et al. Front Oncol.

Abstract

Cancer metabolism is an essential aspect of tumorigenesis, as cancer cells have increased energy requirements in comparison to normal cells. Thus, an enhanced metabolism is needed in order to accommodate tumor cells' accelerated biological functions, including increased proliferation, vigorous migration during metastasis, and adaptation to different tissues from the primary invasion site. In this context, the assessment of tumor cell metabolic pathways generates crucial data pertaining to the mechanisms through which tumor cells survive and grow in a milieu of host defense mechanisms. Indeed, various studies have demonstrated that the metabolic signature of tumors is heterogeneous. Furthermore, these metabolic changes induce the exacerbated production of several molecules, which result in alterations that aid an inflammatory milieu. The therapeutic armentarium for oncology should thus include metabolic and inflammation regulators. Our expanding knowledge of the metabolic behavior of tumor cells, whether from solid tumors or hematologic malignancies, may provide the basis for the development of tailor-made cancer therapies.

Keywords: cancer cell; inflammation; metabolic pathways; therapy targets; tumorigenesis.

Figures

Figure 1
Figure 1
Schematic presentation of strategies utilized in mitochondrial therapeutic targeting. There are several types of mitocans that can target components appending to the outer mitochondrial membrane, to the inter-membrane space, to the cristae membrane and to the matrix. Hexokinase (HK), voltage-dependent anionic channel (VDAC) and adenine nucleotide translocase (ANT) can be targeted by inhibitors that will disrupt main metabolic pathways and the anti-oxidative potential of tumor cells (48, 106, 129); The mitochondrial electron transport chain, producing energy by transporting electrons can be targeted by specific inhibitors (131, 132); BH3 mimetics can impair the function of the anti-apoptotic Bcl-2 and Bcl-x2 family proteins (76, 127); lipophilic cations can directly target the mitochondrial inner membrane and hinder mitochondrial transmembrane potential; compounds that affect directly the tricarboxylic acid cycle (Krebs cycle), affect the electrons stream into the electron transport chain (133); inhibitors that target the conversion of pyruvate (Pyr) to acetyl-CoA (AcCoA) hinder the tricarboxylic acid cycle (67); inhibitors that interfere with the mitochondrial DNA (mtDNA) affecting DNA polymerases or transcript levels (46, 83) (green arrows).
Figure 2
Figure 2
The characteristics of tumor cells and respective targeted therapies. Deregulated metabolism can be targeted with pro-aerobiotic glycolysis inhibitors (52); deregulated cell cycle and increased uncontrolled cellular proliferation can be targeted with pro-apoptotic BH3 mimetics (76, 127); acquired genome instability can be targeted with PARP inhibitors (164); the evasion mechanisms of tumor cell from the anti-tumoral immune response can be controlled by immune activating mAbs (165); enhanced migration capacity of the tumor cell can be targeted with inhibitors HGF/c-Met (166); the angiogenic capacity can be shunted using inhibitors for VEGF signaling; pro-inflammatory properties of the tumor cell can be hindered by selective anti-inflammatory drugs (167).

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