The Warburg effect: a score for many instruments in the concert of cancer and cancer niche cells.

Although Warburg's discovery of intensive glucose uptake by tumors, followed by lactate fermentation in oxygen presence of oxygen was made a century ago, it is still an area of intense research and development of new hypotheses that, layer by layer, unravel the complexities of neoplastic transformation. This seemingly simple metabolic reprogramming of cancer cells reveals an intriguing, multi-faceted nature that may link various phenomena including cell signaling, cell proliferation, ROS generation, energy supply, macromolecules synthesis/biosynthetic precursor supply, immunosuppression, or cooperation of cancerous cells with cancer-associated fibroblasts (CAFs), known as reversed Warburg effect. According to the current perception of the causes and consequences of the Warburg effect, PI3K/Akt/mTOR are the main signaling pathways that, in concert with the transcription factors HIF-1, p53, and c-Myc, modulate the activity/expression of key regulatory enzymes, including PKM2, and PDK1 to tune in the most optimal metabolic setting for the cancer cell.