In normal tissues, the rates of new cell growth and old cell death are kept in balance. Every day thousands of our body’s cells die off. Every day exactly the right number of exactly the right types of cells take the place of those that die off. And if everything is in proper working order, we never even notice.

To illustrate this process, let’s look at the cells of the epidermis (the outermost layer of the skin). The outer layer of the skin is approximately a dozen cells thick. Under normal circumstances, cells at the bottom of this layer, called the basal layer, divide at exactly the same rate as dead cells are shed from the surface. Each time one of these basal cells divides, it produces two cells. One remains in the basal layer and goes on to divide again. The other migrates out of the basal layer and can no longer divide. This way, the number of dividing cells in the basal layer, and the number of non-dividing cells in the outer layer stays the same. Image 1 illustrates normal cell growth.


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Image 1: Normal Cell Growth

In order for this process to unfold with such precision, two important cellular processes must balance each other perfectly:

  • Proliferation
  • Apoptosis

Proliferation refers to the growth and reproduction of cells. Apoptosis or "cell suicide," is the mechanism by which old or damaged cells normally self-destruct. If these carefully balanced processes are disrupted and cells proliferate uncontrollably, fail to die off at the appropriate time, or both, the end result may be cancer. Image 2 illustrates the difference between normal cell division and cancerous cell division.


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Image 2: Normal Cell Division
The Cell Cycle

In order to proliferate both normal and cancerous cells must undergo the process of cell division. This process is the end result of the cell cycle. The cell cycle has two major phases:

  • Mitosis
  • Interphase

Mitosis is the process by which a parent cell produces a pair of genetically identical daughter cells. It is part of the normal cell cycle. The cell cycle is divided into two distinct periods:

  • Interphase (cell growth)
  • Mitotic phase (cell division)

Interphase is the period of a cell’s life when it carries out its normal growth and metabolic activities. It is also the time during which a cell undergoes a closely ordered sequence of activities in preparation for cell division.

Interphase is made up of three sub-phases. During the G1 phase, the cell produces the proteins needed to copy the cellular DNA, which occurs during the second S phase of the cell cycle. There must be two identical copies of the DNA so that one copy is passed to each of the daughter cells. During the final G2 phase, which lies between the replication of the DNA and the beginning of mitosis (when the cell actually divides), the cell produces proteins needed for cell division.

Image 3 illustrates the phases of the cell cycle. See the Focus Box below to learn more about how chemotherapy drugs are designed to disrupt this cycle.


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Image 3: Cell Cycle

Icon image for cancer COEFocus Box: Chemotherapy Drugs

Many chemotherapy drugs are designed to attack cancer cells during a specific phase of the cell cycle where they interrupt the process of cell division. For example, antimetabolites destroy cells that are in the S phase of the cell cycle, while alkylating agents destroy cells in multiple phases of the cell cycle. This is part of the rationale for using combination chemotherapy. Since most tumors are heterogeneous, meaning they are made up of cells in different phases of the cell cycle, they are sensitive to different types of drugs. Combining different chemotherapeutic agents, therefore, increases the likelihood that more cancer cells will be destroyed, which in turn increases the overall effectiveness of the therapy. This approach also allows physicians to gain maximum effect from the treatment without increasing the risk of unpleasant side effects because the dosage of each individual drug is lower. To learn more about the different classes of chemotherapeutic drugs, refer to chemotherapy treatment.

During normal mitosis, the parent cell splits into two perfectly identical daughter cells, each containing one copy of DNA. After mitosis, the new daughter cells will either enter another G1 phase and divide again (like the cells of the basal layer of the epidermis), or they may enter a G0 phase, during which no mitosis-related activity occurs. G0 may last for days (like the cells in the outer layer of the epidermis), weeks, years, or a lifetime. Image 4 illustrates the processes of cell mitosis and division.


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Image 4: Cell mitosis and division.

Cellular differentiation is the process by which a cell changes its structure so that it can perform a specific function. Cells can range from poorly differentiated to well-differentiated. The most poorly differentiated cells (generally called stem cells) are capable of acquiring a range of new functions. Stem cells are important to your overall health. For example, after severe trauma, they provide a pool of cells that can differentiate into specific cell types and repair tissue. Well-differentiated cells are mature, fully developed cells that are ready to carry out their particular function. A good example of cell differentiation is blood cells. There are three major types of blood cells: red blood cells, white blood cells, and platelets. Each has specific characteristics, functions, and life spans, yet all have differentiated from stem cells. Image 5 illustrates the process of cellular differentiation. See the Focus Box below to learn more about the relationship between cell differentiation and cancer.


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Image 5: Cell differentiation

Icon image for cancer COEFocus Box: Cell Differentiation and Cancer

Cell differentiation is important to the study of cancer because a cell’s degree of differentiation is associated with its ability to proliferate. Poorly differentiated cells are highly proliferative, moderately differentiated cells are moderately proliferative, and well-differentiated cells are either unable to proliferate or proliferate at a very slow rate. Aggressive cancers are often characterized by poorly differentiated cells, while less aggressive cancers tend to contain moderately or well-differentiated cells. To learn more about how a cancer cell’s degree of differentiation affects a patient’s prognosis and a physician’s treatment strategy, see the Cancer Staging and Grading section in Cancer 201.

In healthy tissues, the processes of mitosis and differentiation are tightly regulated. This is how the body ensures that only the correct number of cells is produced. The body has two methods for controlling the rate of cell proliferation:

  • Growth factors
  • Contact inhibition

Growth factors stimulate mitosis and/or cellular differentiation. If a cell needs to be replaced (due to damage, natural apoptosis, or some other reason), it will secrete growth factors that stimulate the cell to either undergo mitosis or differentiate.

Contact inhibition stops cells from proliferating. Normally, individual cells maintain a small amount of “personal space”. Under normal conditions, cells that become crowded and begin to touch each other will simply stop growing. Exactly how contact inhibition works is still unknown, however scientists believe that contact between cells triggers the release of growth inhibitory factors. Unlike growth factors, growth inhibitory factors tell cells to stop dividing.

In order for the tissues of the body to maintain such precise control over the growth of its cells, it has developed a system of feedback loops that detect and compensate for deviations from the norm. For every situation controlled by a feedback loop, the body has a set point it recognizes as normal. One example of this is your own body temperature. If your body temperature becomes too warm, a series of physiologic reactions are triggered in an effort to return it towards 98.6 F. If your body’s temperature becomes too cold, a different series of reactions are triggered to warm you up. This is an example of a negative feedback loop. In a positive feedback loop, on the other hand, changes in one direction tend to produce even more change in that same direction.

In the case of normal cell proliferation,when the appropriate number of cells has been produced (and cells begin to crowd each other) growth inhibitory factors trigger a negative feedback mechanism to reduce the rate of cell growth. While positive feedback can occur normally, the production of excess growth factors by cells drives an abnormal positive feedback loop.

Not all abnormally growing cells are cancerous. For example, the term hyperplasia refers to a type of noncancerous growth consisting of rapidly dividing cells, which leads to a larger than usual number of structurally normal cells. Hyperplasia may be a normal tissue response to an irritating stimulus. For example, the callus that forms on your hand when you first learn to swing a tennis racket or a golf club is an example of hyperplastic skin cells. Although hyperplasia is considered reversible, it some cases it indicates an increased risk of cancer. An example is hyperplasia of the lining of the uterus (endometrium).

Dysplasia is another noncancerous type of abnormal cell growth characterized by the loss of normal tissue arrangement and cell structure. Dysplastic cells lose the normal architecture that characterizes normal tissues, and may show physical and chemical changes that distinguish them from their normal counterparts. They may have changes in their DNA, or they may have visible changes in their cell structures (*especially the cell nucleus) that can be seen under the microscope. These visible changes are often useful in detecting dysplasia early, before it progresses, as it sometimes (but not always) does lead to cancer. An example is cervical dysplasia, which may become cervical cancer if left untreated over a long period of time.

The most severe form of dysplasia, carcinoma in situ, can actually be considered a form of cancer. In Latin, the term "in situ" means "in place," so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location (in place) and does not invade surrounding tissue as cancer cells eventually do. Carcinoma in situ, however, is considered more serious than moderate dysplasia because the risk of local invasion is much higher. This is why, when discovered, carcinoma in situ is usually removed surgically. Image 6 illustrates the different types of abnormal cell growth.


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Image 6: Types of abnormal cell growth