Cancer Explained – The Role of Cell Death

Following a recent blog, I received an inquiry from one of our readers. The individual asked whether I could better explain my oft repeated statement that “cancer doesn’t grow too much, it dies too little.” The questioner was puzzled by my assertion that chemotherapy drugs acted to stop cells from growing, while she had come to believe that this was synonymous with killing them. This dichotomy is at the crux of our modern understanding of cancer.

In response, I would like to examine the very basis of what is known as carcinogenesis, the process by which cancer comes to exist.

For more than a century, scientists believed that cancer cells were growing more rapidly than normal cells. They based this on serial measurements of patient’s tumors, which revealed that tumor dimensions increased. A small lump in the breast measuring one-half inch in diameter would be found six months later to be one inch in diameter. And six months after that it was two inches in diameter. This was growth, plain and simple, and so it was reasoned that cancer cells must be growing too much. As such, cancer therapies, per force of necessity, would need to stop cancer cells from growing if they were to work at all.

Dying Cell - lo resAnd then, in 1972, a paper was published in the British Journal of Cancer that described the phenomenon of apoptosis, a form of programmed cell death. Although it would be almost a decade before cancer researchers fully grasped the implications of this paper, it represented a sea change in our understanding of human tumor biology.

Let’s use the example of a simple mathematical equation. Every child would recognize the principles of the following formula:
Tumor mass = growth rate – death rate
This simple equation represents the principle of modern cancer biology. Where cancer researchers went wrong was that they mistakenly posited that the only way a tumor mass could increase was through an increase in the growth rate. However, as any child will tell you, a negative of a negative is a positive. That is, at a given growth rate, the tumor mass can also increase if you reduce the death rate. Thus, the “growth” so obvious to earlier investigators did not reflect an increase in proliferation but instead a decrease in cell attrition. Cancer didn’t grow too much it died too little, but the end result was exactly the same.

It should now be abundantly clear exactly why chemotherapy drugs, designed to stop cells from growing, didn’t work. Yes, the drugs stopped cells from growing, and yes any population of “growing cells” would suffer the effect. But they didn’t cure cancers because the cancers weren’t growing particularly fast. Indeed, the fact that chemotherapy works at all is almost an accident. Contrary to our long held belief that we were inhibiting cell proliferation, chemotherapy drugs designed to damage DNA and disrupt mitosis, were actually working (when they did at all) by forcing the cells to take inventory and decide whether they could continue to survive. If the injury were too extreme, the cells would commit suicide through the process of cell death. If the cells were not severely damaged or could repair the damage, then they carried on to fight another day. None of this, however, had anything to do with cell growth.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

One Response to Cancer Explained – The Role of Cell Death

  1. There are two essential features of cancer that researchers had long considered separate – cell growth and metastasis. The theory of cancer cell growth and replication developed in the 1980′s. Because chemotherapy was considered most effective when cancer cells are dividing the most rapidly, researchers speculated that timing chemotherapy dosage to attack cancer cells at their earliest stage of growth would yield superior results (not a very good theory).

    This is where the thought of “cancer cells don’t grow too much, they die too little” comes about. The concern should be in killing the cancer cell. When the cancer cell is so damaged that it can not longer perform its duty, it will die. Scientists know (or at least they should know) that cancer is not a disease in which cells grow too abundantly, but the failure of cells to expire at their appointed time. Most basic cell biologists acknowledge that cancer is characterized by a failure of programmed cell death (apoptosis).

    One way to look at programmed cell death, is with cell-death assays utilizing functional profiling, which use apoptotic endpoints (point of termination) and also a number of other indicators of programmed cell death. The advantage of this is that they are more reflective of chemotherapy’s actual effects in the human body. Genetic testing can’t and doesn’t do this. Heck, it doesn’t even test any actual anti-cancer agents against your individual cancer cells!

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