Dedicated research in cancer biology over a number of years has now produced a detailed picture of the cancer cell. While investigation is still not complete, many of the molecular and cellular events involved in cancer have now been uncovered. An important challenge has been to translate this revolution in biological insight into actual improvements in the diagnosis and treatment of cancer. In a number of areas, these new insights have already impacted cancer therapy. The future of cancer treatment will continue to be profoundly shaped by these new advances.
One of the central principles in cancer biology is that cancer involves changes or defects in our genes. Genes, which are composed of DNA, contain the key information for each cell in our body. There are an estimated 20,000 to 25,000 genes within each human cell, and this collection of genes is referred to as the genome. In most cells in our bodies, all of this genetic information is packaged in forty-six chromosomes, twenty-three inherited from each parent. A single chromosome therefore contains many thousands of genes, each of which directs the production of proteins such as receptors, enzymes, and structural proteins. Important milestones in the history of science include the demonstration that genes are composed of DNA (1944); the discovery that the structure of DNA is a double helix (1953); and the sequencing or deciphering of the entire human genome (2000).
It is important to distinguish between changes in our genes that are acquired in the course of living and those changes that are inherited at birth from either or both parents. Changes in genes are referred to as mutations. Only a small minority of cancers are predominantly due to mutant genes that are inherited, and these are referred to as familial or hereditary cancers. The majority of cancers develop following a series of mutations in genes at various times after birth or are due to a complex interplay between inherited genes that predispose to cancer and genes with mutations that are acquired during one’s lifetime.
Tumor-Causing and Tumor-Suppressing Genes
Mutations that can lead to cancer typically do so because they increase the function of genes that stimulate cell growth or decrease the function of genes that suppress cell growth. Both types of genes are likely to be important contributors during normal human growth and development. But mutation of these genes can cause otherwise well-regulated processes within a cell to become uncontrolled. If a sufficient number of these changes occur, the cell can become malignant.
Oncogenes One of the seminal discoveries in the field of cancer research is that some of our normal genes can become abnormally activated in various ways, resulting in genes capable of transforming a normal cell into a cancer cell. These activated and cancer-causing genes are called oncogenes (i.e., associated with cancer). The proteins produced by oncogenes are sometimes called oncoproteins.
We carry normal, nonmutated forms of these oncogenes in our chromosomes. In their unaltered, normal state, these genes are referred to as proto-oncogenes and perform useful functions in the cell. However, if they become mutated or overactive (“overexpressed”), the oncogene versions can work with other oncogenes to hijack a normal cell and turn it into a cancer cell.
There are many known oncogenes. They are often named for the types of cancers they first caused in animals when discovered, such as ras for rat sarcoma and neu for neuroblastoma. The mechanisms by which oncogenes, once mutated and activated, cause cancer are diverse. One frequent theme involves oncogenes that produce abnormal amounts of growth factors (molecules that stimulate growth) or growth factor receptors (the partners of growth factors), leading to excessive cell growth and multiplication. Some oncogenes are part of the signaling machinery inside the cell. Activation of these oncogenes also leads to excessive stimulation and uncontrolled growth. Still other oncogenes help cancer cells become immortal; they resist the signal to die by what is called apoptosis, the natural dying process of cells.
There is usually more than one oncogene activated in any given tumor, and these oncogenes may coordinate with each other and with the loss of tumor suppressors to produce cancer.
Tumor Suppressor Genes As their name implies, tumor suppressor genes are normally protective, acting to regulate normal cell growth and multiplication. By doing this, they prevent the unregulated growth that is characteristic of a cancer cell. These genes can sometimes counteract the cancer-predisposing effect of an activated oncogene. If one of these genes is absent or its protein product is unable to work properly, the cancer-producing action of an oncogene may not be completely suppressed and a tumor may then develop.
A number of tumor suppressor genes have been identified. Some are referred to by their biological properties—p53, for example—while others are named for the cancer in which they were first discovered, as in RB (retinoblastoma) and BRCA1 and 2 (breast cancer).
Many tumor suppressor genes were discovered by studying inherited cancers, since abnormal forms of these genes can be transmitted from parents to offspring by either egg or sperm. But they also play important roles in noninherited cancers. Almost all cancers are believed to have a defect in one or more tumor-suppressor genes. A typical colon cancer, for example, may have at least four inactivated tumor-suppressor genes (APC, DCC, MCC, and p53).
The RB gene was the first tumor suppressor gene to be discovered, and retinoblastoma remains a model of a cancer caused by inactivation of tumor-suppressor genes. Retinoblastoma is a rare and sometimes fatal eye cancer occurring mainly in children. There is an inherited form that runs in families as well as a sporadic form that does not have a family connection. In the inherited form, one RB gene derived from one of the parents is defective. Sometime during childhood, the remaining “good” RB gene from the other parent becomes lost or mutated in a retinal cell. Then, because the cell no longer has any functioning RB, it becomes a cancerous retinoblastoma. In the sporadic form, all of the original RB genes were normal at birth. However, if a retinal cell sustains mutations in both genes, then a retinoblastoma can arise.
If detected early, both inherited and spontaneous forms of retinoblastoma are curable with radiotherapy, and vision can be preserved. Genetic probes can detect the abnormal RB gene, identifying children at risk. These children need careful clinical monitoring and frequent eye examinations.
Retinoblastoma occurs when a retinal cell has lost the tumor-suppressing function of both RB genes on chromosome 13. With the inherited form, retinal cells are predisposed at birth, since an inactivating mutation was transmitted by either sperm or egg. In the sporadic form, both genetic defects occur in the retinal cell during development but are not passed on to offspring.
“Multistep” Pathway to Cancer The processes by which proto-oncogenes are activated and tumor suppressor genes are inactivated involve changes to the DNA structure of these genes. As discussed above, abnormal genes can be inherited, such as defective tumor suppressor genes in familial cancers. More frequently, these changes or mutations may arise by exposure to a physical or chemical agent (a carcinogen) that can damage chromosomes or DNA. Radiation in the form of sunlight or X-rays, certain toxic chemicals, and other environmental factors such as cigarette smoke and asbestos are all examples of carcinogens that are known to cause cancers with excessive exposure. Some viruses contain oncogenes that they introduce when they infect cells; an example of this is human papillomavirus, which can cause cervical cancer. Other viruses can also cause DNA damage indirectly, such as by incorporating into chromosomes.
Fortunately, our cells have many safety mechanisms to protect them from becoming malignant despite the mutations that they might sustain. For example, the cell can repair mutations after they occur. However, as we age, the number of mutations that we have accumulated may exceed the cell’s capacity for repair. Also, mutations can occur in the very genes that control DNA repair, thus incapacitating this important function and leading to an accelerated rate of mutation throughout the genome. An example of this is inactivation of the DNA repair gene hMSH2 in colorectal and other cancers. The persistence of activated oncogenes or inactivated tumor suppressor genes that are not repaired will predispose a person to develop cancer in the tissue containing that abnormal cell.
Another safety feature in cells is that there are multiple mechanisms to control cell growth, ensuring that there are backup systems when one mechanism breaks down. Thus, cancer usually does not occur until a series of changes have accumulated, thereby defeating even the backup systems for proper regulation of the cell. In other words, multiple genetic mutations, or accumulated hits, are usually necessary to cause cancer. This is referred to as the multistep model of cancer. As we have seen, these hits would involve activation of oncogenes combined with inactivation of tumor suppressor genes. These genetic hits may accumulate over many months or years because of the effects of various environmental carcinogens on top of inherited susceptibilities. Eventually, if enough oncogene and tumor suppressor gene functions have been altered, this will allow a full-fledged cancer cell to emerge. Additional changes will then allow the cancer cell to gain further abilities that promote the cancer’s effect on the body, such as migrating through tissue, attracting new blood vessels (angiogenesis), resisting the immune system, and other cancer behaviors.
Tests Based on Tumor-Causing and Tumor-Suppressing Genes
Based on this knowledge of the genes that can go awry in the development of a cancer, it has been possible to devise tests that can detect these changes in tumors. This can potentially provide useful information about the future behavior of a particular cancer, including guiding the selection of the most appropriate treatments for that cancer. The following examples illustrate this principle:
Gene Mutation For breast and ovarian cancers that run in families, it is frequently possible to detect the mutant gene responsible. The BRCA1 and BRCA2 genes are tumor suppressor genes that can become mutated; when a mutation is passed from parent to offspring, this leads to an inherited predisposition to these cancers. DNA-based testing to detect mutation of these genes can be performed, which can alert gene carriers that they have inherited this risk. For positively identified gene carriers, close monitoring and/or preventive measures can be implemented.
Gene Amplification Some breast and other cancers are associated with amplification and overexpression of the proto-oncogene called HER-2/neu (also called c- erbB-2). Normally, cells will have two copies of the gene (one copy inherited from each parent). Twenty to 30 percent of breast cancers acquire many additional copies of this oncogene via a process called gene amplification. These cancers have much higher than normal levels of the HER-2 protein, a growth factor receptor, leading to a more aggressive pattern of growth. On the other hand, HER-2–positive cancers can benefit from specific therapies that have been developed to target this oncoprotein (discussed below).
Targeted Therapies
Our understanding of cancer biology has led to a new generation of “targeted therapies” that are designed to counteract the effects of oncogenes or to restore or correct defective tumor suppressor genes. These approaches have already made a significant impact against many cancers. Many additional approaches are being investigated, and this field of targeted therapies has the potential to greatly enhance cancer treatment.
Anti-Oncogene Therapies One example is the use of artificial antibodies (monoclonal antibodies) directed against oncoproteins such as HER-2 and EGFR (epidermal growth factor receptor). For example, trastuzumab (Herceptin), a monoclonal antibody against HER-2/neu, has proven to be useful in the treatment of advanced breast cancers with high levels of HER-2. Newer types of antibody-based therapy include antibodies linked to chemotherapy drugs, radioactive atoms, toxins, and submicroscopic particles containing drugs. These approaches use the antibody portion to deliver potent anticancer agents right to the cancer cell. In addition to antibodies and antibody-based therapies, researchers are pursuing vaccines designed to stimulate the immune system to reject cancer cells containing oncoproteins.
A related approach involves chemical drugs that can inhibit oncoproteins/growth factor receptors such as HER-2/neu and EGFR. These drugs are designed to bind to important sites on these oncoproteins in order to “turn off” their functions. For example, a chromosomal translocation (a form of mutation involving rearrangement of chromosome sections) can create an oncogene known as BCR/ABL, which is an enzyme that leads directly to chronic myelogenous leukemia (CML). A recently developed drug, imatinib mesylate, inhibits the activity of the BCR/ABL enzyme and has proven useful in CML treatment.
Another strategy involves inhibiting the new blood vessel growth (angiogenesis) that tumors establish for themselves. These “antiangiogenic therapies” can block this process, thereby starving tumor cells and stopping tumor growth. (For an in-depth discussion of antiangiogenic therapies)
Tumor-Suppressor Therapies Restoring the activity of tumor suppressors in cancer cells is a rational but difficult strategy. Researchers are attempting to develop drugs that may help to regulate the cell cycle, the process that governs cell growth and multiplication. Other efforts involve replacing the tumor suppressor genes themselves by gene therapy.
Gene Therapy
Gene therapy involves insertion of new genes into cells, thus altering the genetic composition and biological properties of the recipient cells. The first serious attempts at gene therapy for cancer were undertaken in the early 1990s. Now, there are many ways in which gene therapy is being pursued, and many clinical trials around the world are testing these new treatments. The potential for gene therapy is great. Since cancer is generally caused by genes that become mutated and therefore defective, gene therapy can provide a direct “fix” of the problem by replacing the faulty genes with correct versions.
However, there are a number of major technical challenges that must be overcome before gene therapy can be routinely applied to the treatment of cancer. Gene therapy requires a vehicle to deliver the gene to its intended target cell. Delivery systems for genes include modified viruses such as adenovirus, which is one of the viruses responsible for the common cold. Another delivery system involves synthetic particles called liposomes. These systems are still being perfected for gene delivery. Researchers are attempting to improve these delivery systems so that they are safer, more efficient, and capable of “targeted delivery” so that they go to the tumor cells but not normal cells. Meanwhile, clinical studies of gene therapy are focusing on treatment of particular sites in the body, such as confined areas where genes can be delivered more efficiently.
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