Alert Number 229
Date: April 29, 2007
The items in my subject line may sound like a list of unrelated items. Not so, according to the latest article in the prestigious journal “Blood”. The abstract is given below (do write to us if you want to read the full text).
It has long been recognized that in healthy cells glucose metabolism occurs via the “Krebs cycle”, which converts glucose from the food we eat very efficiently into energy, water and carbon dioxide. Mitochondria within each cell play a pivotal role in this crucial function of the body. In cancer cells this smooth process of converting nutrients to energy is very inefficient. Some recent research points to decreased efficiency of mitochondria, even when the cancer cells have many more mitochondria than healthy cells. Another issue with cancer cells is that they are sometimes starved for oxygen, a necessary ingredient for proper function of mitochondria and the Krebs cycle.
Net result, cancer cells have found another way of getting the energy they need, a process called “glycolysis”. This process is no where as efficient as the Kreb’s cycle, but it has the advantage of being able to function even when there is insufficient oxygen. Think of glycolysis as a gas-guzzling souped up SUV, versus a thrifty Prius hybrid of Kreb’s cycle. Glycolysis chews up incredible amounts of glucose and produces much less energy, a very profligate process. It also produces lots of “waste” products, namely lactic acid. Lactic acid is converted in the liver and kidneys, using an enzyme called lactate dehydrogenase.
Now let’s look at the big picture, the consequences of high tumor load:
Here are links to a couple of articles on the role of mitochondria - the power generators in our cells, as well as how CTLs kill pathogens such as viruses and cancer cells.
Blood. 2007 Jan 25.
Inhibitory effect of tumor cell derived lactic acid on human T cells
Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M
Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
A characteristic feature of tumors is high production of lactic acid due to enhanced glycolysis. Here, we show a positive correlation between lactate serum levels and tumor burden in cancer patients and examine the influence of lactic acid on immune functions in vitro. Lactic acid suppressed the proliferation and cytokine production of human cytotoxic T lymphocytes (CTL) up to 95% and led to a 50% decrease in cytotoxic activity. A 24 h recovery period in lactic acid-free medium restored CTL function. CTLs infiltrating lactic acid-producing multicellular tumor spheroids showed a reduced cytokine production. Pre-treatment of tumor spheroids with an inhibitor of lactic acid production prevented this effect. Activated T cells themselves use glycolysis and rely on the efficient secretion of lactic acid, as its intracellular accumulation disturbs their metabolism. Export by monocarboxylate transporter-1 (MCT-1) depends on a gradient between cytoplasmic and extracellular lactic acid concentrations and consequently, blockade of MCT-1 resulted in impaired CTL function. We conclude that high lactic acid concentrations in the tumor environment block lactic acid export in T cells thereby disturbing their metabolism and function. These findings suggest that targeting this metabolic pathway in tumors is a promising strategy to enhance tumor immunogenicity.
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