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Review
. 2024 Dec;31(12):1582-1594.
doi: 10.1038/s41418-024-01402-6. Epub 2024 Oct 23.

Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer

Letizia Lanzetti  1   2
Affiliations
Review

Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer

Letizia Lanzetti. Cell Death Differ. 2024 Dec.

Abstract

By the time a tumor reaches clinical detectability, it contains around 108-109 cells. However, during tumor formation, significant cell loss occurs due to cell death. In some estimates, it could take up to a thousand cell generations, over a ~ 20-year life-span of a tumor, to reach clinical detectability, which would correspond to a "theoretical" generation of ~1030 cells. These rough calculations indicate that cancers are under negative selection. The fact that they thrive implies that they "evolve", and that their evolutionary trajectories are shaped by the pressure of the environment. Evolvability of a cancer is a function of its heterogeneity, which could be at the genetic, epigenetic, and ecological/microenvironmental levels [1]. These principles were summarized in a proposed classification in which Evo (evolutionary) and Eco (ecological) indexes are used to label cancers [1]. The Evo index addresses cancer cell-autonomous heterogeneity (genetic/epigenetic). The Eco index describes the ecological landscape (non-cell-autonomous) in terms of hazards to cancer survival and resources available. The reciprocal influence of Evo and Eco components is critical, as it can trigger self-sustaining loops that shape cancer evolvability [2]. Among the various hallmarks of cancer [3], metabolic alterations appear unique in that they intersect with both Evo and Eco components. This is partly because altered metabolism leads to the accumulation of oncometabolites. These oncometabolites have traditionally been viewed as mediators of non-cell-autonomous alterations in the cancer microenvironment. However, they are now increasingly recognized as inducers of genetic and epigenetic modifications. Thus, oncometabolites are uniquely positioned at the crossroads of genetic, epigenetic and ecological alterations in cancer. In this review, the mechanisms of action of oncometabolites will be summarized, together with their roles in the Evo and Eco phenotypic components of cancer evolvability. An evolutionary perspective of the impact of oncometabolites on the natural history of cancer will be presented.

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Conflict of interest statement

Competing interests: The author declares no competing of interest.

Figures

Fig. 1
Fig. 1. Origin of oncometabolites.
a) Various oncogenes and tumor suppressors (e.g., RAS, MYC, PI3K, mTOR and p53) induce, via different mechanisms, increased glucose uptake and upregulated glycolysis, leading to increased L-lactate production. b) The methylglyoxal pathway is an offshoot of glycolysis, where methylglyoxal is transformed into D-lactate by the action of the enzymes glyoxalase 1 and 2 (GLO1 and GLO2). c) α-ketoglutarate (α-KG) is produced in the TCA by the catalytic action of isocitrate dehydrogenase 1/2 (IDH) on isocitrate. IDH can also generate, with low efficiency, D-2-hydroxyglutarate (D-2HG) (indicated by a dashed line). D-2HG can also be produced physiologically by the promiscuous activity of other enzymes (not shown, see main text). Mutations in IDH lead to the synthesis of gain-of-function IDH proteins (IDH*) capable of metabolizing isocitrate into D-2-hydroxyglutarate (D-2HG) with high efficiency. Note that the enzyme D-2-hydroxyglutarate dehydrogenase (D2HGDH) promptly convert D-2HG into α-KG, under physiological conditions. d) Physiologically, the promiscuous activity of lactate dehydrogenase A (LDHA) or of malate dehydrogenase 1/2 (MDH1-2) can convert α-KG into L-2HG (indicated by a dashed line). This effect is efficiently counteracted by L-2-hydroxyglutarate dehydrogenase (L2HGDH), whose decreased activity, in some cancers, leads to the accumulation of L-2HG. e) Loss-of-function mutations in one of the components of the succinate dehydrogenase (SDH) complex or in fumarate hydratase (FH) lead to the accumulation of succinate and fumarate, respectively. Abbreviations: TCA tricarboxylic acid cycle, AcCoA acetyl-coenzyme A, GLO1/GLO2 glyoxalase 1 and 2, α-KG α-ketoglutarate, IDH isocitrate dehydrogenase 1/2, IDH* mutated isocitrate dehydrogenase 1/2, D-2HG D-2-hydroxyglutarate, L-2HG L-2-hydroxyglutarate, LDHA lactate dehydrogenase A, MDH1-2 malate dehydrogenase 1/2, FH fumarate hydratase, SDH succinate dehydrogenase complex.
Fig. 2
Fig. 2. Molecular mechanisms of action of oncometabolites.
The molecular mechanisms (middle column) through which oncometabolites (left column) modulate various cellular functions (right column) are depicted. In the “molecular mechanism” column, activating and inhibitory functions are boxed in green and red, respectively. The names of the oncometabolites are color-coded together with the connections to the molecular mechanism, to facilitate reading. Details are in the main text. Not all mechanisms/functions described for all oncometabolites are depicted.
Fig. 3
Fig. 3. Oncometabolites and Eco (environmental) phenotypes.
Some of the tumor-relevant phenotypes elicited by oncometabolites through their action on the tumor microenvironment or on the host environment are depicted. Details are in the main text. Abbreviations: M2 TAMs tumor-associated macrophages M2 type, TAMs tumor-associated macrophages, CAFs cancer-associated fibroblasts.
Fig. 4
Fig. 4. Integration of effects of oncometabolites (and their upstream genetic alterations) in cancer evolvability.
In the left panels, a cancer is depicted with its two major components (cancer cells and tumor microenvironment) arbitrarily separated. The communication between these two compartments occurs via various mechanisms. Mechanisms mediated by oncometabolites are shown in the illustration. In the right panels, some selectable advantages conferred by oncometabolites are shown in the two compartments. Not all the actions of oncometabolites are depicted. Note that the various phenotypes might be selected for during different phases of tumor development. Details are in the main text. Abbreviations: CAFs cancer-associated fibroblasts, TAMs tumor-associated macrophages, EMT epithelial-mesenchymal transition.
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