When good cells go bad

The week my family moved from the Appalachian Mountains in Virginia to Atlanta, my great uncle lost his fight against lung cancer.

Like many people in Appalachia, Uncle Carl smoked. When his doctors found the tumor, he underwent the standard chemotherapy treatments and went into remission. A few months later, he went back into the clinic complaining of a pain in his shoulder, and a quick workup determined there was another tumor pressing against his spine. Two days before we moved, I said my farewell to him in hospice care after he was put into an induced coma to ease his pain. Around four hours later, he died.

I don’t know of anyone that doesn’t have a story similar to that one.

In a nutshell, cancer is a disease of uncontrolled cell growth. Most cells in the body don’t divide. With the exception of adult stem cells that serve as a reservoir for new cells to replace old or dead ones, a cell stops dividing once it turns into specific type of cell. For example, once a stem cell becomes a neuron, it stops dividing. Once a cell reaches that point, we refer to it as being post-mitotic. Cancer is what happens when post-mitotic cells start dividing uncontrollably to form tumors. Patients die when tumors interfere with normal body functions enough to kill them.

Cancer is a disease of uncontrolled cell growth. This video was created

by Cold Spring Harbor Laboratory and licensed under a Creative Common

Attribution Noncommercial-No Derivative Works 3.0 US license.

Cancer-related genes fall into two broad categories: tumor suppressors and oncogenes. Tumor suppressors keep cells from dividing or cause cells to kill themselves when they take too much damage. Oncogenes help cells survive or promote cell division. A careful balance between tumor suppressors and oncogenes allow cells to divide when needed but only under strict control.

For a cell to become cancerous, there have to be multiple failures in tumor suppressors and oncogenes. Carcinogens cause cancer by interfering with tumor suppressors and oncogenes, often by mutating them. If high levels of carcinogens bombard a cell for a long time, the number of mutations can overwhelm the redundant fail-safe systems. When that happens, you get cancer.

Cancer is hard to treat because it can take on many diverse forms. Treatments that work for one cancer might not work for others. Some cancers are particularly aggressive and progress rapidly while other cancers are slow to develop. Cancers can kill at high rates or can rarely do so.

On the other hand, many cancers have a lot in common. We’re hoping that if we discover what all cancers have in common, we’ll be able to cure it. Leading the charge is The Cancer Genome Atlas¹ (TCGA), a large group of scientists working together to sequence the genome from tumors isolated from thousands of patients to look for mutations shared by all cancers.

For example, mutations in the TP53 tumor suppressor gene appear to be common in many tumors^2-4. TP53 makes the p53 protein, which monitors the genome for mutations and signals the cell to either repair DNA damage or die so the cell doesn’t become cancerous². p53 is one of the principal tumor suppressor proteins in the cell, and TCGA estimates it’s mutated in half of all tumors^3-4.

In addition to the p53 tumor suppressor, tumors seem to have high rates of mutations in the PIK3CA oncogene. Affecting almost 20% of tumors across all cancer types, PIK3CA mutants signal the cell to divide uncontrollably³. Mutations in other oncogenes like PIK3CA are common in many cancers.

TP53 and PIK3CA are only two genes out of hundreds that may be commonly mutated in cancer. The problem with cancer is that even if we develop drugs that specifically target those proteins, the disease can evade those drugs by accumulating more mutations in different genes. Not all of the cells in a tumor carry the same mutations, and a handful of cells that survive one anti-cancer therapy could continue to divide to cause the tumor to grow back.

Cancer is the bane of developed nations. With the advent of both modern public health practices and antibiotics in the first half of the twentieth century, cancer replaced infectious disease as one of the biggest health threats. In 1971, President Nixon signed the National Cancer Act of 1971, effectively starting what the lay press calls the “War on Cancer⁵.”

Over 40 years later, progress against cancer has been…mixed.

We’ve undoubtedly made enormous advances in treating certain cancers, particularly childhood cancers. Other cancers, such as pancreatic cancer, have roughly the same prognosis they did several decades ago.

If we’ve learned anything from TCGA, it’s that cancers may be infinitely more complicated than we feared. Mutations common to one cancer may not occur in another^3-4. To win the War on Cancer, we need to accept the fact that it’s going to be a long fight. We just have to keep trying.

References

1. http://cancergenome.nih.gov/
2. http://cshperspectives.cshlp.org/content/2/1/a001008.long
3. http://www.nature.com/nature/journal/v502/n7471/full/nature12634.html
4. http://www.nature.com/ng/journal/v45/n10/full/ng.2762.html
5. http://legislative.cancer.gov/history/phsa/1971