The lack of substantial upregulation of serum lactate levels in patients with high serum LDH raises the ques tion whether the lactate that is produced by glycolytic melanoma cells is taken up by metabolically symbiotic tumor cells deriving their energy from OXPHOS before reaching the systemic circulation, which is in support of this metabolic screening library symbiosis model. These data are also in agreement with a previous report, which showed that both glycolysis and OXPHOS dependent tumor cells regulate Inhibitors,Modulators,Libraries their access to energy metabolites. Our study also suggests that advanced melanomas become glycolytic due to their hypoxic state, which might be linked to hypoxia induced stabilization of HIF 1 activ ity. Although HIF 1 regulates the glycolytic program, it also suppresses OXPHOS.

Based upon our data and those of a previously published study, we depict a cartoon that serves to illustrate a working model for metabolic requirements in melanoma. To meet the high metabolic demands associated with melanoma Inhibitors,Modulators,Libraries development, proliferation, migration, and invasion, both OXPHOS and glycolysis are increased in advanced melanoma compared with nevi, which are likely to be metabolically less active tissues. In addition Inhibitors,Modulators,Libraries to the balanced upregulation of these two metabolic pathways, advanced melanoma cells acquire the ability to utilize non glucose sources, such as lactate, as well as the ability to pre vent buildup of acid that may prevent tumor growth. In metastatic melanomas with normal serum LDH, balanced reliance on both OXPHOS and glycolysis is in place until the tumors grow beyond a certain size and thereupon, hypoxic regions develop.

At this point in tumor progression, three distinct melanoma cell populations evolve one that resides in extremely hypoxic Inhibitors,Modulators,Libraries areas, is necrotic, and releases glycolytic LDH isoenzymes, which is the primary cause for increased Inhibitors,Modulators,Libraries serum LDH. The second melanoma cell population resides in hypoxic areas, upre gulates the HIF 1 glycolytic program, and releases lactate and hydrogen ions to maintain normal pH. The third population is in well oxygenated areas and dependent upon OXPHOS by metabolizing glucose as well as lactate, which is released from the nearby glycolytic melanoma cell population. The mechanism that tip the balance towards more glycolysis and less OXPHOS in advanced melanoma are unclear, but may involve, as Otto Warburg described, mitochondrial dysfunction.This loss in mitochondrial function may be functionally reversible or permanently irreversible. Finally, we believe that the findings of our study may be of relevance with respect to the design of future mel former anoma trials.