Characteristics of human cancers: Mutations that are present in the germ cells (egg and sperm) can be passed to the next generation. Mutations that occur in any other cells of the body, called somatic mutations, may affect the cell or tissue in which they occur, but they will not be passed to the next generation. Both germ-line and somatic mutations can cause cancer; it is estimated that approximately 10 percent of cancers are caused by germ-line, or inherited, mutations.
Tumors can be either benign (those that remain localized and noninvasive), malignant (those that invade the basement membrane and underlying tissue), or metastatic (those that shed cells that seed tumors in other locations of the body). Progressive degrees of abnormality are observed in benign, malignant, and metastatic tumors, suggesting that cancer develops in a stepwise process.
Cancers can arise in almost all tissue types in the body, although approximately 80 to 85 percent of human cancers arise from epithelial cells those cells that cover internal and external surfaces of the body, including the linings of internal organs and glands.
The incidence of many types of cancer varies worldwide, and epidemiologic studies show that environment is the largest factor in variations in cancer incidence from country to country. Indeed, a number of environment and lifestyle elements, tobacco smoking being the most obvious, are known to be strongly correlated with the incidence of certain types of cancer. In 1975, it was shown that many chemicals that are capable of causing mutations in deoxyribonucleic acid (DNA) are also capable of causing cancer in laboratory animals. Later research showed, however, that not all chemicals that cause cancer also cause mutations. Therefore, other mechanisms besides DNA mutation must be involved in at least some cancers.
Gene expression and signaling pathways: For the cells of an organism’s various tissues (lung and bone, for example) to display complex, tissue-specific characteristics, large groups of genes must be coordinately expressed while other genes must be repressed. Specialized proteins known as transcription factors are responsible for achieving this coordinated expression. Transcription factors bind to specific DNA sequences in the control region of each gene. The transcription of most genes is controlled by the binding of several distinct transcription factors in the gene’s control region. A single transcription factor can affect the expression of multiple genes that contain its binding sequence in their control regions. In cancer cells, a defective transcription factor may affect the expression of multiple genes, the end result of which is to create a cancer cell from a normal cell.
Normal cells within tissues and within an organism communicate with each other in a regulated fashion through a multitude of chemical signals and pathways. Disruption of these normal signaling pathways is an important component of the formation of cancer. In normal cells, signals are transmitted through the various pathways in a number of ways: by a change in the level of activity of signaling molecules by noncovalent modifications, changes in the concentration of a signaling molecule inside a cell, or the direction of signaling molecules to particular locations within the cell.
Oncogenes: Normal cells contain a class of genes involved in the regulation of growth and division called proto-oncogenes. A proto-oncogene can mutate into a version that is permanently activated and causes uncontrolled cell division, one of the hallmarks of a cancer cell. The transformation of a proto-oncogene into an oncogene may involve a change to the structure of the protein itself or an increase in its expression. A change involving the structure of the protein itself may require only very small changes; in some cases a single base pair mutation is sufficient. A change involving an increase in expression often occurs through increasing the number of copies of the gene in the DNA. There are several ways that amplification of a gene can occur: by enhanced replication of a chromosome segment that carries its DNA or by the breaking away of such a chromosome segment to form a small chromosome-like particle that is capable of replicating independently.
Scientists have identified more than one hundred oncogenes. They include growth factors, proteins that signal a cell to divide; growth factor receptors, proteins on the cell surface to which growth factors bind; signal transducers, proteins that make up the signaling pathways between the growth factor receptor and the cell nucleus; and transcription factors.
Tumor-suppressor genes: The class of tumor-suppressor genes includes a large number of genes whose protein products are involved in a multitude of normal cellular functions that in some way regulate a cell’s division and reduce the chance that the cell will become cancerous. Tumor-suppressor genes in cancer cells are often inactivated through mutation or other mechanisms. An inherited increased risk of developing a specific type of cancer in some families is often the result of the presence of a defective tumor-suppressor gene. It is the loss of function of tumor-suppressor genes that can lead to cancer, in contrast to oncogenes, which have gained functions or lost the ability to be controlled in their mutant form.
The protein product of a particularly important tumor-suppressor gene, called TP53, causes cessation of cell division and even programmed cell death (apoptosis) in normal cells if the process of cell division malfunctions. In this way the cell’s well-being is monitored, protecting the organism from the effects of runaway division of wayward cells by activating the apoptotic pathway in such cells. Apoptosis is an orderly process in which the DNA of a cell is degraded and the cell itself fragmented into smaller pieces that are taken up by nearby white blood cells whose job is to clean up such debris. Loss of the ability to undergo apoptosis allows cancer cells to survive a variety of environmental stresses and signaling imbalances. The TP53 gene in the DNA of cancer cells often carries mutations that cause it to malfunction; more than 90 percent of small-cell lung cancers and more than 50 percent of breast and colon cancers have been shown to be associated with mutant forms of TP53.
Normal cells throughout the body grow and divide to generate two daughter cells in a highly organized and controlled series of events called the cell cycle. A subclass of tumor-suppressor genes controls cell-cycle events in normal cells. Control mechanisms at various steps of the cell cycle function to ensure that a preceding step is completed before the next step can begin. These control mechanisms are inactivated in many types of cancer cells, allowing them to divide in an unregulated fashion. A particularly important tumor-suppressor gene in this class is the retinoblastoma (RB1) gene. The protein product for which the RB1 gene codes, pRb, is affected in most if not all types of human cancer cells. Loss of normal regulation of the signaling pathway of which pRb is a component leads to unrestrained cell proliferation.
Cell immortalization: The ability of a cell to divide indefinitely, called cell immortalization, appears to be a characteristic of all cancer cells. This ability has been shown to be related to the structures of the ends of chromosomes, called telomeres, which are composed of several thousand repeats of a six-base-pair sequence element. Every time a cell duplicates its DNA, the telomeres are shortened by fifty to one hundred base pairs, with the result that normal cellular DNA has the capacity for a finite number of replications. The ability to indefinitely maintain telomere length has been observed in virtually all types of cancer cells, the majority of which accomplish this by increasing the expression of the enzyme, telomerase, which is responsible for synthesizing telomeres.
Angiogenesis: All cells depend on the availability of oxygen and nutrients for their growth and survival. Virtually all cells in a tissue must be located close to a capillary blood vessel that can deliver nutrients and take away metabolic waste products. For a cancer cell to progress to a macroscopic tumor, it must acquire the ability to induce the formation of new blood vessels, a process called angiogenesis. In normal cells, various negative and positive signaling pathways control the angiogenic process. Cancer cells appear to induce angiogenesis in a number of steps that change the balance of angiogenesis inducers and inhibitors during tumor development.
Metastasis: Most types of human cancer will at some point undergo metastasis, the process whereby new tumors are seeded at distant sites from the primary tumor. Metastases are responsible for approximately 90 percent of all cancer deaths. Metastasis involves tumor cells leaving the primary tumor, invading adjacent tissues, and from there traveling to sites where they are able to settle and start the growth of new tumors. The primary route of metastasis is through the circulatory system, although metastatic cancer cells may also spread through lymph ducts to lymph nodes. Sometimes cancer cells traveling through the circulation form small obstructions that lodge in the arterioles and capillaries of various tissues. Complex interactions between the metastasizing cell and the microenvironment of the host tissue in which it lands govern the process of invasion into the tissue and colonization to form a metastasis in a process that is not well understood.
Cancer cells that metastasize do not appear to have undergone major changes in their DNA compared with other cells in the original tumor. However, cancer cells that possess metastatic potential have alterations in several classes of proteins involved in the attachment of cells to their surroundings in a tissue, which render them less able to form such attachments. Cancer cells with metastatic potential may also have an increased ability to degrade proteins in their immediate environment. Metastasizing cells from various types of cancers tend to spread preferentially to some organs; for instance, prostate and breast cancers have a strong tendency to metastasize to the bone marrow, and colon cancer has a strong tendency to metastasize to the liver. The reason for this phenomenon is not well understood.
Genomic instability: It has been estimated that multiple genetic changes, perhaps five to seven, are needed for the development of a full-fledged human cancer. A normal cell has numerous control and repair mechanisms that ensure the fidelity of DNA replication and, therefore, that the occurrence of mutations is rare. Malfunctioning of components of these control and repair mechanisms, such as TP53, leads to the observed chromosomal instability and variability of cancer cells. Genetic instability is pervasive in human cancer cells, which commonly exhibit various types of aberrantly structured chromosomes: the loss of entire chromosomes, the presence of extra copies of chromosomes, or the fusion of part of one chromosome with part of another. These chromosomal abnormalities disrupt normal DNA sequence and arrangement and probably help explain how precancerous cells acquire the necessary mutations to render them cancerous.
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