The Biology of Cancer

Precis
This article provides a brief explanation of the biology of cancer, including its biological and molecular causes. A number of complex scientific terms (identified in bold type) are explained in the text.

What is Cancer

Cancer is an abnormality in a cell's internal regulatory mechanisms that results in uncontrolled growth and reproduction of the cell. This sounds simple, but there are probably more regulatory interactions occurring within a cell than there are interactions among people in New York City in any given day.

Normal cells make up tissues, and when these cells lose their ability to behave as a specified, controlled and coordinated unit (dedifferentiation) the defect leads to disarray amongst the cell population. When this occurs, a tumor is formed. (More about this later.) Cancer is a term describing a large variety of disorders of proliferation. The specific disorder may vary from tissue type to tissue type. A single tumor may even have different populations of cells within it with differing processes that have gone awry.

Malignant versus Benign

A tumor can be classified as malignant or benign. In both cases, there is an abnormal aggregation and proliferation of cells. In the case of a malignant tumor, these cells behave more aggressively, acquiring properties of increased invasiveness. Ultimately, the tumor cells may even gain the ability to break away from the microscopic environment in which they originated, spread to another area of the body (with a very different environment, not normally conducive to their growth) and continue their rapid growth and division in this new location. This is called metastasis. Once malignant cells have metastasized, achieving cure is more difficult.

Benign tumors have less of a tendency to invade and are less likely to metastasize. They do divide in an uncontrolled manner, though. Depending on their location, they can be just as life threatening as malignant lesions. An example of this would be a benign tumor in the brain, which can grow and occupy space within the skull, leading to increased pressure on the brain.

Correction of Abnormalities

Corrections of the various cellular abnormalities in tumor cells could potentially prevent or reverse cellular proliferation, leading to cure of disease. There are numerous reasons why this is so difficult, but the primary explanation is that we do not yet have a sufficient understanding of all the processes that go on inside a cell at the molecular level. Without this knowledge, we lack the ability to "tell" the cancerous cells to simply "behave." Instead, we must achieve our cures by killing the cancerous cells.

Another problem is that cells (including non-cancerous ones) naturally acquire mutations as they reproduce. Rapidly-reproducing groups of cells mutate at an even higher rate. Cells have certain "machinery" within them which helps to correct these mutations as they occur during reproduction, but cancerous cells often lose this ability (more about this below). The end result is that a single tumor may contain a heterogeneous group of cells with different cellular "features." Even if we understood the mechanism for proliferative tendency within a tumor, not all the cells in a particular tumor are the same. Many other cells types that are slightly different exist in a population of cancer cells, and these cells would also have to be targeted by our treatment strategies.

Genetic Research

There are many areas of current active intense research aimed at addressing these problems. A major endeavor is the Human Genome Project (HGP), the national coordinated effort to characterize all human genetic material contained in human cells. The HGP's ultimate goal is to discover all the more than 80,000 human genes and render them accessible for further biological study.

Some of these genes have already been implicated in tumor growth. Oncogenes are genes in the cell that, once activated, help drive the cell's division in an uncontrolled manner. Similarly, there are some known tumor suppressor genes which are normally active in a cell to prevent uncontrolled growth, but which become defective or are "turned off" in some cancer cells.

Picture provided with permission of the DOE Human Genome Project

Causes of Genetic Abnormalities

There are a number of potential factors causing human genetic abnormalities. We now know that some acquired mutations can turn on oncogenes or can inhibit tumor suppressor genes. These mutations occur in the cell's chromosomes (the 46 "units" or "packages" within a cell which contain its genetic material) during normal cellular division. There are names for some of these types of chromosomal mutations, which you may see in your further reading, such as "chromosomal translocations", "inversions", "deletions", "amplifications" or "point mutations." (The specifics of these different chromosomal abnormalities are beyond the scope of this article, but suffice it to say that these abnormalities lead to various kinds of genetic disarray.)

Cellular Function and Damage

While genetics is the key to understanding the transformation of normal cells into tumors, we must also understand how genetic mutations affect cellular function.

In order to understand cell proliferation, understanding the role of the cell cycle is crucial. All cells in the body reproduce (though some more slowly than others). For instance, the top layer of your skin is continously lost and replaced through your lifetime. For a cell to reproduce itself, it needs to pass through this "cycle" of events, which include doubling its genetic material and increasing the amounts of cellular "machinery", so that when the cell divides in two each cell has enough basic materials to survive and reproduce.

The orderly progression of events through this cell cycle is dependent on specific timing mechanisms. Oncogenes and tumor suppressor genes directly control many aspects of the cell cycle. When these genes become mutated through a chromosomal abnormality, they can cause the cell cycle to continue in an uncontrolled fashion by turning off various mechanisms which normally prevent the cell from replicating in a disorderly way.

Differentiation

Each cell in your body derives from one original cell (formed when the egg and the sperm came together). As this cell reproduces into more cells and forms a fetus, they diversify (differentiate) into different tissue types (muscle, bone, cartilage, nerve, stomach lining, and so on). In the end, the human body is composed of perhaps hundreds of kinds of cells. One of the curious things (not well understood by scientists) is that once a cell becomes a nerve cell (for example) it cannot then change into a muscle cell, even though the original cell from which it derived did in fact have that ability. It has differentiated.

Differentiated cells have another property -- they "stick together" in well-defined ways (into microscopic and macroscopic tubes, sheets or strings) within your body, to form the various tissues. After chromosomal abnormalities occur and cells becomes dedifferentiated (or undifferentiated), these cells can lose their tendency to "stick together" at the cellular level. The scientific term for this is a "loss in contact inhibition."

Apoptosis

Apoptosis, referred to as programmed cell death, is another intricate piece of the cell cycle. Apoptosis is a distinct form of death that is a programmed event and occurs in response to certain stimuli. Apoptosis is essential for normal tissue development. In addition, this system allows cells to self-destruct after detecting DNA damage rather than perpetuating mutations that might be lethal to the whole organism.

The cell's decision to grow and repair the DNA damage or to induce apoptosis is not understood, but may be related to the degree of DNA damage. The p53 gene is a key participant in this process. The loss of p53 function can result in both inappropriate progression through the cell cycle after DNA damage and survival of a cell that might have otherwise died. Since p53 is at the core of cell cycle stability and apoptosis, it is not surprising that it is the most commonly mutated gene in human cancers, comprising defects in more than 50% of all tumors.

The pRb gene also plays an important role in preventing the cell cycle from continuing in an uncontrolled manner. (It provides a so-called "checkpoint" in the cell cycle and prevents a cell from cycling further unless certain stringent criteria have been met.) When the pRb gene is mutated, the cell could lose this important step which controls cell reproduction. This in turn would lead to enhanced cell proliferation, thus enhancing malignant transformation of the cell.

Summary

Cells may become malignant when the genes responsible for apoptosis become mutated. The mutated genes provide:

1. Less than usual inhibition of cell cycle progression (tumor-suppressor genes),
2. Enhanced drive through the cell cycle (oncogenes)
3. Increased anti-apoptosis signals; and/or
4. Decreased pro-apoptosis signals

As we acquire a better understanding of cell death, methods that exploit apoptotis for clinical gain may be developed. These methods may involve the selective activation of apoptosis in tumor cells and not in normal tissue; correction of the apoptotic defects in cancer cells by somehow restoring the p53 gene; or preventing apoptosis in normal tissues with agents that protect normal tissues from damage by radiation (radioprotection) and chemotherapy (chemoprotection) so higher doses of radiation could be delivered to tumor cells without affecting normal human tissues.

Conclusion

There are hundreds of known factors implicated in the cause of cancer, and hundreds more that are still dubious or unknown. Many are under investigation, or have been implicated previously but are now dismissed as major factors (proximity to electrical high power lines, for instance). Before cures can be found by way of molecular genetics, we will need to understand the complete interaction of the cell and its surroundings.

It is unlikely that a single cause for cancer will ever be identified. Common mechanisms leading toward the development of all cancers may and do exist. The identification and prevention of these abnormal processes is probably the most likely way we will be able to reduce cancer rates. Once a cancer forms, however, many different strategies need to be employed to interrupt these cellular processes, and remove and disable the abnormal cells. These strategies, by necessity, will differ depending on tumor types, locations and other tumor and host factors.