Oncogenic Alterations in Metabolism
This review article discusses the fundamental changes in cell metabolism between normal cells and cancer cells. Tumor cells have different metabolic requirements than normal cells; for example, tumor cells typically experience hypoxic environments (either because their size has become too large for efficient O2 diffusion or if they are too far away from a blood vessel). As a result, it is shown that many glycolytic pathway proteins are upregulated as a mechanism to deal with these different physiological environments. For example, hypoxia inducible transcription factor (HIF-1) is shown to be directly upregulated in response to hypoxic conditions. This transcription factor controls the expression of various glycolytic pathway proteins including lactate dehydrogenase and phosphofructokinase L that allow the cancer cell to survive in low O2 conditions.
The tumor microenvironment also has other effects on cell metabolism including angiogenic factors and apoptosis. For example, hypoxia and hypoglycemia stimulate VEGF and other factors for angiogenesis.
The effect of tumor microenvironment on cell metabolism is interesting because these conditions can effectively used in potential future cancer therapeutics. For example, as a result of the upregulation of glycolytic pathway proteins, high lactid acid (from the result of glycolysis and anaerobic respiration) levels are typically found around active tumors (The Warburg Effect). This high acidic environment and other upregulated glycolytic pathway proteins can prove to be effective markers for cancer therapeutics. For example, a Natural Killer Cell or macrophage may be engineered to migrate towards high acidic environments (or to recognize certain glycolytic markers) and may thus facilitate in fighting cancer. The upregulation of glycolytic pathway proteins can also serve as a potential target in preventing developing cancer cells from adapting to their tumor microenvironments. For example, if developing cancer cells are unable to upregulate a vital Glut4 transporter for glycolysis, they may not be able to survive or grow for long.
4 comments:
See also: http://scienceblogs.com/transcript/2008/03/from_metabolism_to_oncogenes_a.php
The paper shows many interesting characteristics of cancer cells. In the paper, it also says that humans can engineer some natural killer cells migrate to the acidic environment in order to kill cancer cells. However, even if natural killer cells are closer to the cancer cells, will they kill cancer cells automatically because they do not receive any signals to kill cancer cells.
This is definitely a potentially promising area of research, as programming cells to recognize the glycolytic environment of tumor cells can be an effective way to target and destroy tumors. However, there are probably many other cells in the body which also upregulate glycolysis, such as muscle cells, and care must be taken so that these cells are not targeted also. Specificity is the key.
What I always find puzzling is that upregulated glycolytic pathway proteins don't trigger an innate or humoral immune response. Even thought they are self proteins you would think there would be some signal for aberrant expression.
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