Cancer cells: the initial step to the dark side

If you keep on feeding a normal cell 24/7 with glucose; it would become saturated with glycogen. However, when there is no glucose, the cell reverses its cellular processes to break down glycogen and produce glucose. This is a healthy circular feedback loop: Lots of glucose --> Glycogen; no glucose --> Breakdown glycogen.

Cancer cells are highly adept at taking up glucose (1, 2, 3, 4). There are multiple glucose transporters in the plasma membranes; those proteins are over-expressed in cancer cells. But, in contrast to normal cells, cancer cells don't store glucose as glycogen. Their whole system is geared to take up glucose and shuttle it to the production of proteins and nucleic acids. They process all the "food" that they ingest to produce another cancer cell. 

What drives this insanity? Why are the normally circular glucose pathways uni-directional? 

One proposal is that the cell is starved for acid ions (H+) (1, 5, 6).

Cancer cells' primary abnormality may be that they are too efficient at getting protons out of the cell. This makes the pH in the cytoplasm alkaline. In fact, cancer cells are known to have an unusually alkaline pH when compared to non-cancerous cells (cytoplasmic pH 7.12-7.7 vs 6.99-7.05, respectively).  

This high - or alkaline - pH in the cytoplasm stimulates the enzymes that break down glucose (glycolysis). In particular, rate-limiting enzymes in glycolysis such as phosphofructokinase are 100 times more active when the pH is more alkaline (1, 5).

The cell heeds the call of an alkaline pH and starts furiously breaking down glucose into lactic acid to bring the pH to a more acidic level.

However, as I noted, cancer cells are adept at getting rid of H+ to the extracellular space. They have a superabundance of proton-removal machinery, like the Na/H+ exchanger (NHE1 - 1, 5) ). This creates an unfortunate duality: a highly acidic extracellular space, while the cytoplasm is alkaline.

Lactate transporters need  the proton ions to efficiently transport lactate out of the cell. Some of the lactate is shuttled out, but the extra lactate in the cell has to go somewhere. To prevent the gridlock, the cells shuttle the breakdown products of glucose into other avenues. Those products are shuttled into other systems - like the Pentose Phosphate Pathway (PPP). This leads to the formation of nucleic acids (6, 7).

To add insult to injury, many of the enzymes in the PPP system  are also more active in an alkaline environment. Thus, an alkaline environment perpetuates the dark side of cellular metabolism:

• A hyper-active glycolytic system to produce more protons (which are unfortunately quickly kicked out of the cell) 
• shuttling of glucose by-products into revving up  the nuclear machinery.

To prove this thesis (the power of changing the pH in the cytoplasm to an alkaline level and its effect on the cell), there have been multiple studies that have shown that: 

• the first step in malignant transformation of normal cells is the activation of the proton exchangers (like NHE1).
• This is followed by cytosplasmic alkalinization (1, 5).
• The increase in the cytoplasmic pH is followed by an increase in glycolytic pathways (5). 

Interestingly, hypoxia has exactly the same effect on cells as an alkaline cytoplasmic pH. With hypoxia, the cell moves into anaerobic glycolysis (breakdown of glucose without oxygen). The net result is the same.

The cell overproduces lactic acid, the extracellular space becomes acidic, and the cell pushes the intermediate metabolites from the breakdown of glucose into other pathways.

In fact, chronic hypoxia is enough to induce malignant transformation in cells . Thus, both oncogenes and hypoxia seem to promote the systems that create a rise in cytoplasmic pH as an early step in the malignant transformation process (5).

Unfortunately, in the cancer evolution, tissue hypoxia develops as the mass of tumor cells has a dysfunctional microcirculation. Not only do cancer cells have internal dysregulation of their metabolism (with the alkaline pH); their extracellular space - with an acidic pH and a hypoxic milieu - perpetuates ongoing production of glucose breakdown products, which further exacerbates the cancer pathology (8, 9, 10, 11, 12, 13, 14).

The pH homeostasis of a cell is one of the most important signals of health (15). Normal cells and their enzymes have well-defined ranges of acidity or alkalinity for optimal activity.  

Clearly, when the cytoplasmic pH range is abnormally high, cancer can develop. A major reason for this is that the enzymes that are trying to correct the alkaline pH are more active in alkaline pH ranges. That makes perfect sense, except that those enzymes rev up the metabolism of the cell to generate more protons but to no avail: the enzymes cannot successfully fill a leaky cytoplasmic bucket with enough protons.

Thus, over-expression of proteins that keep the pH high in the cytoplasm perpetuates the pathology and is a clear promoter of the cancer phenotype.