Cancer

A Genetic Disease

Cancer is the result of changes in the genetic material of a cell that cause the cell to gradually lose the ability to grow in a regulated fashion. These changes can be brought about by contact with harmful environmental agents or by inheritance of genes leading to a genetic predisposition.

Cancer risk increases with age, as the probability of accumulating mutations in the DNA increases with time. Environmental factors include lifestyle (e.g., smoking), diet (e.g., saturated fats from red meat), and exposure to certain chemicals (e.g., asbestos, benzopyrenes), ionizing radiation (e.g., X-rays, radon gas), ultraviolet radiation (e.g., sun, tanning beds), and certain viruses (e.g., human papillomavirus, Epstein-Barr virus). Heredity also plays a role in oncogenesis, as mutations in certain genes increase the probability of developing certain types of cancer. For instance, women who inherit a mutated copy of the BRCA1 or BRCA2 gene have a greatly increased probability of developing breast cancer at a young age.

Classification of Cancer Types

The term "cancer" is general, in that it represents a large group of related diseases that arise from neoplasms. A neoplasm is classified by the type of tissue in which it arises and the stage to which it has progressed. Neoplasms are also called tumors. Not all tumors are cancerous. A tumor that grows in one place and does not invade surrounding tissue is called benign. In contrast, invasive tumors are called malignant. These are cancerous.

Benign or Malignant Tumor

Whether a tumor is benign or malignant determines how potentially life-threatening it is. Benign tumors are usually harmless, although their location may be serious (if surgery to remove the tumor would carry significant risk). These tumors are not considered cancerous, are relatively slow-growing, and usually are encased within a fibrous capsule.

Malignant tumors (cancers) have great potential to spread, or metastasize, to other sites in the body. These tumors are fast-growing and aggressive, and they invade neighboring healthy tissue. They therefore are considered life threatening.

Type of Tissue

The body consists of many different organs, which in turn are composed of several different types of tissues. There are three major categories of tissue-related tumor types: carcinoma, sarcoma, and leukemia/lymphoma. There are also other specialized tumor categories, such as those of the central nervous system (e.g., brain tumors).

Carcinoma.

This is the largest category, containing about 90 percent of all cancers, and it consists of neoplasms derived from epithelial cells. Epithelial cells make up the outer layers of the skin. They also line the inner structures of organs such as the lungs, intestines and testes, as well as complex tissue such as the breast.

Sarcoma.

These are solid tumors derived from all connective tissues except the bloodforming tissues (these are the leukemias and lymphomas). These tumors account for about 2 percent of all cancers. They occur in such tissues as muscle, bone, and cartilage.

Leukemia and Lymphoma.

This group contains about 8 percent of all cancers, including blood cancers that originate from the marrow (leukemias) and from the lymphatic system (lymphomas). This group also includes other nonsolid tumors of the bone marrow and lymphatic system, such as myeloma, which affects plasma cells—a type of white blood cell found in the marrow and in other tissues.

Type of Cell

Classifying a tumor by the type of cell from which it is derived is slightly more complex than classifying it by the type of tissue, since there are so many cell types. The main cell types include adenomatous cells (which are ductal or glandular cells), basal cells (found at the base of the skin), myeloid blood cells (granulocytes, monocytes, and platelets), lymphoid cells (lymphocytes or macrophages), and squamous cells (flat cells). Therefore it is possible for a cancer classified by its site of origin to be broken up into one of several cell types. For example, a skin cancer could be either a squamous cell carcinoma, a basal cell carcinoma, or a melanoma (from a pigment-producing cell).

Site of Origin

Solid tumors are firm masses that develop from a neoplasm's originating organ, such as the brain, esophagus, kidney, liver, lung, ovary, pancreas, prostate, or testis. Tumors of the blood-forming tissues and lymphatic systems are not solid and tend to remain free and circulating even when malignant. Some of the common forms of cancer are listed in the table above.

Cancer Progression

There two main steps in cancer progression: the initial growth of the cancer and the subsequent spread via metastasis. Solid tumors are subject to the physiological constraints of biological systems: Without nutrients and oxygen, they will die. Therefore a solid tumor is initially limited in size to no larger than 1 to 2 millimeters in diameter (about the size of a small pea).

For a tumor to become aggressive, it needs to be able to nourish the cells at the center of its mass that are too far away from blood vessels. This is achieved by angiogenesis. Through mutation, a few cancer cells may gain the ability to produce angiogenic growth factors. These growth factors are proteins that are released by the tumor into nearby tissues, where they stimulate new blood vessels to grow into the tumor. This allows the tumor to rapidly expand in mass and invade surrounding tissue. It also provides a route for the cancer cells to escape into the new blood vessels and circulate throughout the body, where they can lodge in other organs forming metastases.

The most common way for a cancer to metastasize is through the lymphatic system. The lymphatic system is a network of channels throughout the body that carry a tissue fluid called lymph.

When a primary neoplasm metastasizes to another location, its cell type does not change. If leukemia metastasizes to the liver and develops a tumor, the tumor will display the characteristics of the leukemia, not those of a liver cancer. In some cases this can help physicians determine the original site of a tumor.

Genes Altered in Tumors

Although each cell in the body maintains itself and carries out its specific function, it is part of a large colony of collaborating cells that constitute the whole organism. A cell communicates with its surrounding cells by releasing chemical messages, in a process called signal transduction. These messages bind to specific receptor proteins on the surface of the surrounding cells. The gene expression of these cells is changed as a result of the messages.

A hyperplastic cell or a cancerous cell will stimulate neighboring cells to grow by secreting growth factors. Several types of genes can be mutated in tumor cells: oncogenes, tumor suppressor genes, DNA repair genes, and genes involved in cell mortality.

Oncogenes.

These genes are involved in signal transduction, and some are involved in the various phases of the cell cycle. Mutations in cell-cycle regulation or signal transduction can "push" the cell into dividing rapidly and without regard to its surroundings. Over 100 oncogenes have been identified so far. They include genes such as ABL1 (Abelson murine strain leukemia viral homolog) and EGFR (Epidermal Growth Factor Receptor).

Tumor Suppressor Genes.

These genes inhibit cell division, working in a manner opposite to that of the oncogenes. Surrounding cells secrete growth-inhibitory signals that help prevent proliferation. These growth-inhibitory signals work in conjunction with tumor suppressor genes. If a tumor suppressor gene is mutated, proliferating cells can ignore these inhibitory messages. This group includes the genes p53, BRCA1, and BRCA2.

DNA Repair Genes.

These are the genes that provide the cell with the ability to sense and correct damage to the DNA. Damage to the DNA can be caused by radiation, chemicals, ultraviolet light, or errors in transcription. If these errors are not corrected, they accumulate in the genome and can quickly increase the chance that a cell will become cancerous. Repair genes include those in the DNA-ligase and excision-repair gene families.

Genes Involved in Cell Mortality.

A normal cell can only undergo about forty divisions, after which it dies or enters senescence. If a tumor had this limitation it would be very limited in its size, as it would reach its forty divisions relatively quickly. This process is controlled by the enzyme telomerase, which maintains the telomeres (repetitive DNA sequences at the ends of chromosomes that shorten after each round of DNA replication, until they reach a length that causes the cell to die) by not allowing them to shorten. Some cancer cells become immortal as a result of mutations in the telomerase gene, causing the telomeres to be extended indefinitely, allowing the cell to continue dividing without limit. Other mutations affect the process of apoptosis.

Cancer does not usually arise by a single event. Instead, two or more "hits" are needed to convert a well-regulated cell to a cancer cell. This is the case because each cell contains two copies of each gene, one inherited from each parent. Most cancer-causing mutations cause a loss of function in the mutated gene. Often, having only one functional copy is enough to prevent disease. Thus, two mutations are needed.

This can be illustrated by looking at retinoblastoma, a common cancer of the retina. The affected gene (called the retinoblastoma gene) is a tumor suppressor. Spontaneous mutations are rare, but since there are many millions of cells in the retina, several will develop the appropriate gene mutation over the course of a lifetime. It would be very unlikely, though, for a single cell to develop two spontaneous mutations (at least in the absence of prolonged exposure to carcinogens), and thus spontaneous retinoblastoma is very rare.

If, however, a person inherits one copy of an already-mutated gene from one parent, every cell in the eye starts life with one "hit." The chances are very high that several cells will suffer another hit sometime during their life, and so the chances are very high that the person will develop retinoblastoma. Since inheriting a single copy of the mutated gene is so likely to lead to the disease, the gene is said to show a dominant inheritance pattern.

Future Directions in Diagnosis and Treatment

The increased knowledge of cancer at the biochemical and genetic level has led to many advances toward better diagnosis and treatment of cancer, including the design of more specific drugs that are less toxic to normal tissue. This includes the use of antisense molecules, which are nucleic acid sequences that are complementary to the mRNA of a target gene. As the two sequences are complementary, they anneal and thus the mRNA is blocked from being translated into a protein, resulting in less of that particular protein being produced (such as growth factor receptors). Drugs specific in blocking angiogenesis are able to control the growth and spread of tumors, especially when used in combination with other treatments.

SEE ALSO AMES TEST; ANTISENSE NUCLEOTIDES; APOPTOSIS; BREAST CANCER; CARCINOGENS; CELL CYCLE; COLON CANCER; DNA REPAIR; MUTAGEN; MUTATION; ONCOGENES; SIGNAL TRANSDUCTION; TELOMERE; TUMOR SUPPRESSOR GENES.

Giles Watts

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