Tumor Genetics:
The Core of the Problem

Cancer is a genetic disease that consists of different combinations of genetic alterations. It takes several different types of alterations to contribute to malignant changes in the cell. Most cancers are sporadic and not hereditary.

The abnormal behaviors demonstrated by cancer cells are the result of a series of either mutations in key regulatory genes or epigenetic changes. The cells become progressively more abnormal as more genes become damaged. Often, the genes that are in control of DNA repair become damaged themselves, rendering the cells even more susceptible to ever-increasing levels of genetic mayhem.

As already discussed in Hallmarks 2000, a great deal of research has led to a better understanding of the multiple genetic mutations that lead to cancer. The following is a short recap.

Types of Genetic Changes:

	DNA Mutations - changes to the sequence of nucleotides in DNA Translocations - alterations of large amounts of DNA, often at the level of the chromosome. Gene Amplification - production of many copies of a gene or set of genes at one location on a chromosome Inversions - segments of DNA are released from a chromosome and then re-inserted in the opposite orientation Duplications/Deletions - a gene or group of genes may be copied more than one time within a chromosome or lost entirely Aneuploidy - the loss or gain of entire chromosomes Epigenetic Changes - changes to the DNA and chromatin that do not change the sequence
Image courtesy of the Genome Management Information System, Oak Ridge National Laboratory

• There are usually multiple redundant pathways that lead to the aberrant behavior of cancers. Knocking out one may not solve the problem


• There are often unanticipated feedback loops, so that when a pathway is knocked out, alternative pathways are accentuated.


• Tumor cells are inherently unstable so the cells evolve to resist treatments that may, temporarily, seem to be working

The difference between 2000 and today is that we now know that in addition to oncogenes and tumor suppressor genes, most cancers acquire several other key mutations and/or changes that enable the cancer to progress.

 

Cancer Stem Cells (CSC)

Embryonic stem cells that have the potential to produce all types of cells are believed to have considerable medical potential and have been highly publicized, but the research that is required to realize their potential is still relatively new and remains controversial.

Less well recognized is that more specialized stem cells are present in adult organs. Like embryonic stem cells, they have unlimited potential to regenerate but can only regenerate cells related to their organ of origin. For example, breast stem cells generate new breast cells and lung stem cells generate new lung cells. An increasing number of scientists believe that these adult stem cells are at the heart of cancer, and the key to successful treatment.

According to the stem cell hypothesis, a small proportion of cancerous tumors are made up of stem cells, which are more resistant to current therapies.

		While current therapies may kill the non-stem portion of cancers, unless the stem cells are killed, the cancer will grow back. Thus, new therapies are being developed that will target stem cells.
Image courtesy of Dr. Peter Znamenskiy

Not only is finding the source of cancer cells necessary for successful treatments, but also if current treatments of cancer do not properly destroy enough CSCs, the tumor will reappear. This includes the possibility that someone treated with chemotherapy, for example, will have only chemotherapy-resistant CSCs left behind so the ensuing tumor will most likely also be resistant to chemotherapy.

 

CISN Summary:

Cancer evolves when an array of genetic changes take place in cancer genes, leading to greatly increased cell growth and escape from apoptosis (programmed cell death).

• Cancer cells have lost their ability to divide in a controlled fashion. A tumor consists of a population of rapidly dividing and growing cancer cells.


• Mutations rapidly accrue within the population. These mutations (variations) allow the cancer cells (or sub-populations of cancer cells within a tumor) to develop drug resistance and escape therapy.


• Cancer stem cell research is an ongoing area of research that has not yet been agreed on by all as being critical to the treatment of the disease.