SummaryCancers grow and spread by a process akin to evolution.
A cancer cell accumulates mutations, each of which can give the cell a growth advantage over its neighbors. This single cell will divide to populate the tumor until another cell with an even better growth advantage crops up. At that point, the more aggressive cell reproduces rapidly, taking over the tumor. It’s survival of the fittest, with every cell for itself.
But all these cancer-promoting mutations do not occur at once. At each stage, cancer cells face selective pressures that drive their evolution. Cells near the center of a growing tumor, for example, face shortages of oxygen and nutrients. And pioneering cells that escape the main tumor must adapt to life in a foreign tissue if they are to establish outposts in other organs of the body. Only those cells that acquire mutations that help them adapt to the changing environment and outcompete their neighbors will survive to divide and conquer.
For a cell to become cancerous, it must amass quite a few mutations—sometimes three or four but often many more. And these mutations must occur in the correct genes and in the correct place within those genes. That combination is, fortunately, statistically rare. What’s more, the process of acquiring multiple mutations can take decades. Most of us die from other diseases before cancer has had time to develop.
Although cancer-causing mutations can occur in several kinds of genes, all these mutations ultimately promote cell growth and survival, allowing cell division to outstrip cell demise. Bert Vogelstein and his colleagues have spent years identifying the specific genes and mutations responsible for colon cancer. This type of cancer is a good one to study because the resulting tumors can be removed and analyzed at various stages in their development, revealing the genetic progression that leads to cancer. Vogelstein’s studies of colon cancer have opened a window on cancer evolution and led to a deeper understanding of the formation and development of all cancers.
Loss of Control
The growth of a cancer is often likened to a car speeding out of control. Whether the car’s brakes are cut or its gas pedal is stuck, the vehicle hurtles forward, no longer responding to the driver’s attempts to control its speed. In a sense, the same thing happens in tumors, which form when normal cells lose the ability to control their growth and division. That loss of control can result from a number of different mutations. Cancer cells can activate genes that encourage proliferation—akin to giving the car too much gas. Such growth-promoting genes are called oncogenes, from onkos, the Greek word for tumor or mass. Cancer cells can also eliminate genes that inhibit replication—cutting the brakes that normally keep cell growth in check. These growth-inhibiting genes are called tumor suppressors. Mutations that activate oncogenes or inhibit tumor suppressors all promote cancer by upsetting the normal balance between cell birth and cell death.
Mr. Bad Wrench
Cancers can also speed their growth by acquiring mutations in genes that normally fix DNA damage. By disabling their cellular repair systems—the equivalent of hiring an inept mechanic—cancer cells further tip the balance in their favor. Shutting down DNA repair allows any mutations that crop up to be preserved. Thus mutations in repair genes promote the accumulation of additional mutations, fueling the evolution of cancer.
Defects in DNA repair genes are responsible for one of the most common forms of hereditary colon cancer, called hereditary nonpolyposis colorectal cancer (HNPCC). Patients with HNPCC inherit a defective copy of an important repair enzyme that fixes the errors that sometimes occur as cells copy their DNA. Once cells lose their ability to repair these replication errors, mutations can accumulate in many genes, including tumor suppressors and oncogenes. Patients with this genetic defect develop one or two tumors that then progress rapidly to full-blown cancer.
A Model Cancer
Colorectal tumors begin as benign polyps—small outgrowths in the lining of the colon. Then, as mutations occur in genes that normally balance the relative rates of cell birth and cell death, the tumors grow larger. Eventually, the cells break away from the tumor and colonize the liver, lungs, and other tissues in the body. At this point the tumor is considered a malignant cancer.
In many colon cancers, a mutation that inactivates a tumor-suppressor gene called APC is the first, or at least a very early, step in cancer progression. APC mutations can be detected in small benign polyps at the same high frequency as in large malignant tumors, suggesting that they occur early in the process. The loss of APC activity gives the affected cell a growth advantage, allowing it to form a colony of cells that divide more rapidly than they die. The increased proliferation leads to the growth of a polyp.
Mutations that activate an oncogene called Ras take place later than those that knock out APC. Ras mutations are rare in small polyps but common in larger ones. Activation of oncogenes such as Ras enables the tumor to grow larger still. Elimination of other tumor-suppressor genes, such as p53, comes much later. Finally, additional changes—still poorly understood—permit the tumor to become invasive and spread to other tissues. Mutations that eliminate the activity of DNA repair genes, which can occur at any time, further help drive the process forward.
Putting Knowledge to Work
Knowing the genetic path that a particular cancer follows could someday help physicians better treat individual patients. By determining the genetic defects responsible for a specific cancer, physicians might be able to select the therapy that will be most effective at eliminating that cancer. Furthermore, each cancer-causing gene that researchers identify can serve as a target for the development of more specific therapies that will wipe out cancer cells while leaving healthy cells unharmed.