Increased Lactate Production in Malignancy

Created on Sun, 06/14/2015 - 07:44
Last updated on Wed, 08/02/2017 - 01:28

This is by no means common as a complication of malignancy, but needs to be mentioned as a sidenote.

Malignant cells are known to have an unnaturally elevated rate of glycolysis even in the presence of oxygen; and in many solid tumours the inside parts of the tumour are woefully hypoxic.  

The excess of glycolytic activity has been attributed to an overexpression of glycolytic enzymes and to the decreased regulation of these enzymes by the increasingly deranged and insulin-unresponsive cancer cells. The use of this inefficient aerobic glycolysis has been named "Warburg effect", and appears to be a reflection of the change in focus in the cancer cells' priorities, from efficient metabolism to accelerated proliferation (Vander Heiden et al, 2009). The precise explanation for how it is supposed to help the cancer cells proliferate is unclear, and there are multiple theories discussed in the article by Liberti et al (2009)

Not only that, but of course the liver is frequently involved, and we all know what happens to lactate clearance when you decrease hepatic blood flow and oxygenation.

The real question in these situations is how one goes about treating this lactic acidosis, given that the cancer may not be treatable?

The study of haematological malignancies referenced below advances two management modalities; one is dialysis.

Of course, but surely that is cheating.  You aren't solving the problem, you are merely contributing an exogenous organ of clearance.

Another method which is mentioned is the titration of the lactate with bicarbonate, waiting for the chemotherapy to work- but this is known to be counterproductive, as intracellular acidosis actually tends to slow lactate production (and thus intracellular alkalosis  will cause the production of lactate to increase!).

Lastly, a method is mentioned where insulin is administered together with dextrose; the insulin in this scenario facilitates the conversion of pyruvate to acetyl-CoA, thus removing lots of pyruvate from the cell and thus shifting the lactate-pyruvate ratio in a way which favours the conversion of lactate to pyruvate. This is just fine if the tumour is insulin-responsive; of course if it is not, then all you are doing is feeding the tumour more glucose, straight  into the glycolytic pathway which produced all that lactate in the first place. You don’t want to feed the tumour.

 

References

Sillos EM, Shenep JL, Burghen GA, Pui CH, Behm FG, Sandlund JT. Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature. Cancer 2001;92(9):2237-46.

De Groot, R., et al. "Type B lactic acidosis in solid malignancies."  Neth J Med. 2011 Mar;69(3):120-3.

Vander Heiden, Matthew G., Lewis C. Cantley, and Craig B. Thompson. "Understanding the Warburg effect: the metabolic requirements of cell proliferation." science 324.5930 (2009): 1029-1033.

Liberti, Maria V., and Jason W. Locasale. "The Warburg effect: how does it benefit cancer cells?." Trends in biochemical sciences 41.3 (2016): 211-218.