Cancer cells produce higher amount of lactate. But can it be useful for the cancer cells and how can they utilize it?
Hi, the increase in lactate produced by tumor cells is a result of their altered metabolic state. There are many pathways affected by this change in metabolism and as such, lactate appears to serve several different functions in the tumor environment including but not limited to immune evasion, potential antioxidative effects, and promotion of angiogenesis. Here is a nice review for your reference. Good luck.
Cancer Res. 2011 Nov 15;71(22):6921-5. doi: 10.1158/0008-5472.CAN-11-1457.
Lactate: a metabolic key player in cancer.
Hirschhaeuser F1, Sattler UG, Mueller-Klieser W.
Hi, the increase in lactate produced by tumor cells is a result of their altered metabolic state. There are many pathways affected by this change in metabolism and as such, lactate appears to serve several different functions in the tumor environment including but not limited to immune evasion, potential antioxidative effects, and promotion of angiogenesis. Here is a nice review for your reference. Good luck.
Cancer Res. 2011 Nov 15;71(22):6921-5. doi: 10.1158/0008-5472.CAN-11-1457.
Lactate: a metabolic key player in cancer.
Hirschhaeuser F1, Sattler UG, Mueller-Klieser W.
I completely agree with Stacey
Earlier, lactate production was known to be one of the consequence of increased anaerobic glycolysis by cancer cells due to multiple reasons. This effect is also known as Warburg effect. Now, recent studies have shown that lactate level can be used to predict metastasis and overall survival of patients. In the cancer research paper (as mentioned by Stacey), it is clearly mentioned that lactate induced the production of hyaluronan by fibroblasts cells.Moreover, lactate also induce the secretion of VEGF by endothelial cells, which leads to increased migration and angiogenesis in solid tumors. Being antioxidant in nature, Lactate neutralized ROS levels, which further reduces the effect of radiation and other therapeutic approaches.
Cancer cells tend to exhibit aerobic glycolysis, which is also referred to as Warburg effect. Lactate is the major metabolic product of glycolysis and it has been believed to contribute to the acidic tumor stroma in which fibroblasts change their phenotype into alpha-SMA-positive cancer-promoting ones. It has recently been reported, however, that the glyclysis product is heterogeneously uptake in three patterns as follows.
Three models of lactate shuttling in cancer.
(A) The reverse Warburg effect occurs when cancer cells secrete hydrogen peroxide, which is thought to generate a pseudo-hypoxic environment in the stroma. In turn, this induces HIF-1α, MCT4 expression, and glycolysis in stromal fibroblasts, which then efflux excess lactate via MCT4. Stromal-derived lactate is then imported by tumor cells via MCT1 and used as an oxidative metabolite. (B) In metabolic symbiosis, tumor cells in hypoxic regions of the tumor efflux lactate through MCT4, which is then imported by tumor cells in less hypoxic regions via MCT1 and used as an oxidative metabolite. This shuttling facilitates delivery of glucose to the hypoxic regions of the tumor. (C) In the vascular endothelial lactate shuttle, tumor cells efflux lactate via MCT4, which is imported by vascular endothelial cells by MCT1. Lactate is then converted to pyruvate, which activates HIF-1α and NF-κB/IL-8 signaling.
Article Targeting lactate metabolism for cancer therapeutics
The answer on this query can be found in the article: Ponisovskiy M.R., (2010), “Cancer metabolism and the Warburg effect as anabolic process outcomes of oncogene operation”, Critical Reviews in Eukaryotic Gene Expression, 20 (4), 325 – 339.
The presence of lactate in tumor tissue specifically in the tumor stroma shows hypoxia within the tumor due to malformation of the architectural peritumoral vessels during angiogenesis.
Here is a recommended paper if you want more informations at the molecular level : http://www.sciencedirect.com/science/article/pii/S0022519314005578
Try to read this paper too : http://www.sciencedirect.com/science/article/pii/S0092867411001279
Hi everyone....
I agree with all above theories... Just, I have one question to everyone...The tumor produced more lacatate, its well known theory by Warburg effect. Tumor cells effulux the intracellular lactate by MCT4 to maintain the intracellular pH. The extracelluar lactate modulate the tumor microenvironmet. it helps for the migration and metastatisis ect... There are several inhibitor for MCT4 also. My question is if we increase the intracelluar lactate by altering metabolic pathway or supplimetation of lactate to cancer cell. we have done that and we found intracellular lactate was increased and it induced cell death. but other people are used lactate to see the metastasis. so our research is little contradict with others. I would like get some suggestion for this issue.
Thanks in Advance.
Cancer metabolism is characterized by excessive shift normal balance catabolic & anabolic proccesses into excessive anabolic endoergonic processes, versus excessive shift balance catabolic & anabolic processes into excessive catabolic exoergonic processes in inflammation processes. Therefore cancer metabolism obtains great quantity energy due to accumulation energy into lactic acids production in condition of anaerobic catabolic processes of oxidative phosphorylation - glycolysis. This mechanism of cancer metabolism is the basis of Warburg effect mechanism (see the elucidations in the details the article: Ponisovskiy M.R., (2010), Cancer metabolism and the Warburg effect as anabolic process outcomes of oncogene operation, Critical Reviews in Eukaryotic Gene Expression, 20 (4), 325 – 339).
As concerning to influence of lactic acids on extracellular and intracellulsr PH, there is stability of cellular Internal Energy as well as stability Internal Energy of an orgainsm according first law of thermodynamics. It's meant that there are stabbility of such main parameters: 1) Temperature 36,4⁰C - 36,9⁰C by which all enzymes operate; 2) Stable cellular basophylic chemical potential in cytoplasm due to staining cells and stable PH=3,75 in blood and neurolymph of an organism; 3) Stable osmotic pressure 285 ± 5 mil-osm / kg H2O, corresponding to 0,14 - 0,15 M sodium chloride or the other univalent ions; 4) colloidal-oncotic ressure 18 - 25 mm Hg, corresponding to human serum albumin solution up to 300 gram per liter. Thus stable cellular PH, which defines basophylic chemical potential of cytoplasm, is the result of hydrocarbonaceous buffer (main buffer) combined with lactic buffer and the other organic acid - alkaline buffers, calculated by Henderson - Hasselbach formula. Just this PH calculation is not depended on the concentration of cations and anions. However the changes concentrations cations and anions would be able to violate stable indices of osmotic pressure and colloidal - oncotic pressure, if it is the closed thermodynamic system, i.e. static model non exchaged by energy and substances with environment, being caused destruction Internal Energy of this system due to increase entropy according second law of thermodynamics. But both an organism and cells of an organism are the open thermodynamic systems, i.e dynamic model exchanged by energy and substances with environment, exhibiting permanent an organism's growth and cellular proliferations and simulaneusly an organism and cells death (Apoptosis) due to permanent inflow and outflow energy and substances, that cause minimisation gain of entropy maintaining stability of the open thermodynamic systems both an organism and cells of an organism according to famous Prigogine theory.
Can you give me idea is that any difference between intra and extracellular lactate production by cancer cells.
Lactic acids accumulate great energy for the taking up huge quantity energy by cancer cells which need an energy for accelerated proliferative processes!!! [see Ponisovskiy M.R., (2010), Cancer metabolism and the Warburg effect as anabolic process outcomes of oncogene operation, Critical Reviews in Eukaryotic Gene Expression, 20 (4), 325 – 339).].
Lactic acids accumulate great quantity energy for expression excessive anabolic endergonic processes which need for irrepressible cancer cellular cycle in Warburg effect mechanusm. [see Ponisovskiy M.R., (2010), Cancer metabolism and the Warburg effect as anabolic process outcomes of oncogene operation, Critical Reviews in Eukaryotic Gene Expression, 20 (4), 325 – 339).].
Lactate metabolism is the primary metabolism in cancer cells. Cancer cells have utilize large amount of glucose to produce lactate. lactate involves in energy supply and as a carbon source in cell multiplication.
Converting excess pyruvate to lactate shifts the metabolism of cancer cells (CCs) from TCA+oxphos to glycolysis, that in turn, enables them to be alive in hypoxic and nutrient-deprived tumor microenvironment (TME). Moreover, through efflux of extra lactate to TME, CCs increase the acidity of TME, that prevent invade of immune cells (1). Meanwhile, we should consider the help of cancer associated fibroblasts by providing lactate for CCs(2).
There is a novel view on cancer cell metabolism based on cellular energy. Recently, I have published it in a WOS-indexed journal. Kindly, I present it to all dear experts in the field of cancer cell metabolism. You can find it in the attachment. It would be my pleasure to hear the opinions of all experts.
1. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell metabolism. 2016 Jan 12;23(1):27-47.
2. Avagliano A, Granato G, Ruocco MR, Romano V, Belviso I, Carfora A, Montagnani S, Arcucci A. Metabolic reprogramming of Cancer associated fibroblasts: the slavery of stromal fibroblasts. BioMed research international. 2018;2018.
Hi! I congratulate the authors on these publications, but I don't see the sense that cancer tumor intense excessive anabolic metabolism turns from TCA to glycolysis in order to "enables them to be alive in hypoxic and nutrient-deprived tumor microenvironment". Such metabolism in cancer tissue does not correspond to famous Warburg effect "aerobic glycolysis" of cancer tissue metabolism.
Dear Dr. Ponizovskiy
I appreciate for your kind reply.
According to the literature, reprogramming from OXPHOS to glycolysis enables the cancer stem cells to survive in hypoxic tumor microenvironment,
to produce ROS, and to enhance their stemness (1,2). This notion is not in contrast with the Warburg’s theory.
1. Folmes CD, Dzeja PP, Nelson TJ, Terzic A. Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell (2012) 11(5):596–606. doi:10.1016/j.stem.2012.10.002
2. Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell (2013) 23(3):316–31. doi:10.1016/j.ccr.2013.01.022
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