Lactate: A Metabolic Key Player in Cancer

Abstract

Increased glucose uptake and accumulation of lactate, even under normoxic conditions (i.e., aerobic glycolysis or the Warburg Effect), is a common feature of cancer cells. This phenomenon clearly indicates that lactate is not a surrogate of tumor hypoxia. Tumor lactate can predict for metastases and overall survival of patients, as shown by several studies of different entities. Metastasis of tumors is promoted by lactateinduced secretion of hyaluronan by tumor-associated fibroblasts that create a milieu favorable for migration. Lactate itself has been found to induce the migration of cells and cell clusters. Furthermore, radioresistance has been positively correlated with lactate concentrations, suggesting an antioxidative capacity of lactate. Findings on interactions of tumor metabolites with immune cells indicate a contribution of lactate to the immune escape. Furthermore, lactate bridges the gap between high lactate levels in wound healing, chronic inflammation, and cancer development. Tumor cells ensure sufficient oxygen and nutrient supply for proliferation through lactate-induced secretion of VEGF, resulting in the formation of new vessels. In summary, accumulation of lactate in solid tumors is a pivotal and early event in the development of malignancies. The determination of lactate should enter further clinical trials to confirm its relevance in cancer biology. Cancer Res; 71(22); 6921-5. Ó2011 AACR.

The acidic microenvironment as a possible niche of dormant tumor cells

“…Furthermore, the isoform of pyruvate kinase M2, usually highly expressed in tumor cells under activity of oncogenic transcription factor c-MYC, may slow down aerobic glycolysis, which results into accumulation of up-stream precursors for anabolic demand of proliferating cells [9]. c-MYC is also involved in promotion of many of glycolytic enzymes [10], together with Akt pathway, which enhances glycolysis through activation of hexokinase 2, phosphofructokinase 1 and 2 and expression of glucose transporters [11][12][13]. The generated pyruvate, together with the entry of glutamine into tricarboxylic acid (TCA) cycle, cooperates to the promotion of anabolic reactions needed for cell division.…”

1009 Serum lactate dehydrogenase and survival following cancer diagnosis

“…Lactate dehydrogenase (LDH) is the enzyme responsible for the conversion of pyruvate to lactate during glycolysis (Hirschhaeuser et al, 2011). It is expressed in all tissues and its A and B subunits, coded by two different genes LDH-A and LDH-B, combine to construct five isoenzymes (LDH1 to LDH5) with selective distribution among tissues and in serum (Maekawa, 1988).…”

Modulating Roles of Amiloride in Irradiation-Induced Antiproliferative Effects in Glioblastoma Multiforme Cells Involving Akt Phosphorylation and the Alternative Splicing of Apoptotic Genes

“…Earlier studies have shown that the antiproliferative effects of amiloride in several cancer cell types may result from apoptosis (Park et al, 2009;Chang et al, 2011aChang et al, , 2011b. In contrast, other agents, for example, lactate and gemcitabine, are reported to, respectively, increase radioresistance (Hirschhaeuser et al, 2011) and decrease radiosensitivity (Salem et al, 2012). The current study of GBM8401 glioblastoma cells showed a larger antiproliferative effect in amiloride-treated cells with IR post-treatment compared to amiloride-treated cells with IR pretreatment.…”