Cancer heterogeneity is not compatible with one unique cancer cell metabolic map

Abstract

The Warburg effect and its accompanying metabolic features (anaplerosis, cataplerosis) are presented in textbooks and reviews as a hallmark (general characteristic): the metabolic map of cancer. On the other hand, research articles on specific tumors since a few years emphasize various biological features of different cancers, different cells in a cancer and the dynamic heterogeneity of these cells. We have analysed the research literature of the subject and show the generality of a dynamic, evolving biological and metabolic, spatial and temporal heterogeneity of individual cancers. We conclude that there is no one metabolic map of cancer but several and describe the two extremes of a panel from the hypoxic to the normoxic state. The implications for the significance of general 'omic' studies, and on therapeutic conclusions drawn from them and for the diagnostic use of fractional biopsies is discussed.

Figure 1

Simplified scheme of ‘the metabolic map of cancer cell'. The classical normal cell metabolism in the presence of O₂, from glucose to pyruvate, mitochondrial acetyl-CoA, and through the Krebs cycle to CO₂: black lines. The glycolytic Warburg pathway, from glucose to pyruvate and lactate: red lines. The pathways, from glutamine, acetate, and fatty acids to aminoacids, nucleotides and fat: green lines. The Krebs cycle: yellow lines. accos, acetylcoA synthase; aldo, aldolase; Atp cl, adenosine triphosphate citrate lyase; eno, enolase; FaCoA, fatty acyl-CoA; ffk, phosphofructokinase; gapdh, glyceraldehyde phosphate dehydrogenase; glnase, glutaminase; glut1, glucokinase; glutdh, glutamic acid dehydrogenase; gpi, glucose phosphate isomerase; hk, hexokinase; ldh, lactate dehydrogenase; mct, monocarboxylic acid transporter; me, malic enzyme; oxalo, oxaloacetate; pc, pyruvate carboxylase; pdh, pyruvate dehydrogenase; pdhk, pyruvate dehydrogenase kinase; pck2, pyruvate carboxykinase; pgk, phosphoglycerate kinase; pkm2, pyruvate kinase m2; tpi, triose phosphate isomerase.

Figure 2

Diversity of cells in cancer. EMT, epithelial mesenchymal transition.

Figure 3

The two states metabolic map. Expression and Biology CA, carbonic anhydrase; CAF, cancer-associated fibroblasts; LDH, lactate dehydrogenase; HIF, hypoxia inducible factor; Lox, lysyl oxidase; MCT, monocarboxylic transporter; PDH, pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; PKM2, pyruvate kinase M2; TOMM20, translocase of outer mitochondrial membrane 20.