20.4 : Adaptive Mechanisms in Cancer Cells

Cancer cells exhibit a mutator phenotype characterized by defective DNA repair mechanisms that lead to higher than normal mutation rates. Their tolerance to mutations even in the critical cell cycle genes confer them with survival advantages over normal cells. 

For example, normal cells stop dividing once they contact another cell, in a phenomenon known as contact inhibition. However, some cells can mutate to overcome contact inhibition and pile up on top of each other, forming a tumor mass. 

Nonetheless, these tumor cells cannot continue to proliferate forever. At some point, they may undergo replicative cell senescence, a phenomenon where cells stop dividing after a certain number of cell divisions. 

Thus, some tumor cells mutate further to overcome this hurdle and become cancerous. First, they increase their rate of cell division to compensate for the loss of cells due to cell senescence. Secondly, they can evade apoptosis, resulting in the prolonged survival of old and damaged cells.

The tumor grows, the cells in the interior of a large tumor receive less oxygen - a phenomenon called hypoxia. This limits the ability of the cells to grow and can trigger cell necrosis inside the tumor. 

Cancer cells overcome this challenge with two advantageous mutations. First, they promote angiogenesis - the process of new blood vessel formation around the growing tumor that can supply more oxygen and nutrients to the cells. 

The second is a metabolic switch from oxidative to glycolytic metabolism. 

In normal cells, glucose is metabolized into pyruvate by glycolysis. Under aerobic conditions the pyruvate is metabolized via oxidative phosphorylation to produce a large but slower ATP yield. Under anaerobic conditions, such as during intense muscle activity, cells metabolize pyruvate into lactate by anaerobic glycolysis with low but rapid ATP yield. 

To fuel rapid growth, cancer cells uptake 100 times more glucose than normal cells which is converted into pyruvate via glycolysis. Then, the pyruvate is quickly metabolized into lactate by anaerobic glycolysis irrespective of oxygen availability. This phenomenon is called the Warburg effect.

Even though anaerobic glycolysis is less efficient than oxidative phosphorylation, it provides rapid bursts of ATP for cancer proliferation.