Cancer and Genetics Help (page 2)
Introduction to Cancer
Cancer is a genetic disease resulting from multiple mutational events and chromosomal rearrangements. These mutations alter the normal functioning of a cell so that it takes on the following characteristics: (1) it becomes immortal, i.e., it is capable of unlimited cell division, and (2) it becomes independent from normal cellular controls that limit growth and division some cancers become invasive by spreading to other tissues, in a process called metastasis. One cancer cell is capable of dividing into a clonal mass of cells called a tumor. Tumors are not necessarily life-threatening (e.g., warts or galls) and may occur in both plants and animals. Plants do not have cancers because their cell walls prevent metastasis of tumor cells.Oncogenesis is the process by which a normal cell becomes cancerous; oncology is the study of cancer.A neoplasmis a population of potentially cancerous cells growing out of control. If the neoplasm is confined to its place of origin and has no tendency to recur after removal, it is a benign neoplasm. If it metastasizes from its site of origin, it becomes a life-threatening malignant neoplasm.
Some oncogenic mutations may be inherited, and/or be induced by environmental exposure to mutagens that damage DNA. Oncogenic mutations may also occur spontaneously. A carcinogen is any agent (e.g., mutagenic chemicals, ionizing radiations, and certain viruses) that can promote a cancerous state. Aside from the irritant fibers of asbestos, all carcinogens are thought to be mutagenic (causing damage toDNA), but not all mutagens are carcinogenic.
EXAMPLE 11.10 Xeroderma pigmentosum is a genetic syndrome characterized by extreme sensitivity to ultraviolet light and the tendency to develop multiple skin cancers. It is inherited as an autosomal recessive trait that produces a defective enzyme. Individuals with this genotype are unable to repair ultraviolet-induced DNA damage. This disease provides strong evidence that cancer originates in cells that have sustained permanent damage to DNA.
EXAMPLE 11.11 A type of blood cell cancer known as chronic myelogenous leukemia is associated with a reciprocal translocation involving the tip of the long arm of chromosome 9 and a portion of the long arm of chromosome 22. The chromosome 22 that bears a piece of chromosome 9 is called a Philadelphia chromosome (Example 7.23). A cellular protooncogene called c-abl (normally located on chromosome 9) becomes activated to oncogenic status when translocated to chromosome 22. A homologus gene (v-abl) exists in the highly oncogenic Abelson murine (mouse) leukemia virus.
Cancer is generally conceded to involve at least two major steps. The first step, termed initiation, results from a single exposure to a carcinogen or the spontaneous generation of a mutation. The second step, called promotion, involves one or more exposures to the same initiator or even to unrelated substances called promoters that complete the conversion of a cell to the neoplastic state. The promotion stage is a gradual process, often requiring many weeks in rodents and years in humans. Phorbol esters are among the most well-known promoters. Further heritable changes of an unknown nature are thought to occur during the promotion phase. Some substances [e.g., benzo(a)pyrene and polycyclic hydrocarbons, at relatively high doses] can both initiate and promote tumor formation. Mutations in certain genes, such as BRCA-1, may predispose a person to cancer requiring fewer promoters to create a cancerous state.
Many carcinogens must undergo metabolic activation. In this process, enzymes in various tissues, especially those in the liver convert the inactive precarcinogens into active carcinogens (see Supplementary Problem 10.10). Not all species have the enzymes necessary to convert a given precarcinogen into a carcinogen; hence, such a species would not be susceptible to induction of cancer by that substance.
Types of Mutations
There are two different types of mutations that can lead to cancerous growth. The first type is a gain-of-function mutation in a gene that normally promotes cell growth and division. Cell division is controlled by many different genes, some stimulatory others inhibitory. Interference with the timing at which these genes act, the amount of gene product produced, or the activity of the gene product could lead to cancer. Most cells in the body are terminally differentiated and are not actively dividing; thus, cell division genes are generally turned off. If they become inappropriately activated, uncontrolled cell division may result. These types of cancer-causing genes are called oncogenes. Normal cellular counterparts of oncogenes are called protooncogenes. Some of these genes are carried by oncogenic viruses and are sometimes designated as v-oncogenes (for viral).V-oncogenes can be linked to potent promoters that lead to their inappropriate and high-level expression, which can lead to deregulated cell division. The second type of mutation is a loss-of-function mutation in a tumor suppressor gene. Tumor suppressor genes have normal roles as suppressors of cell growth and division. These are the genes that are turned on in inactive cells. If inappropriately turned off, the cell may enter the cell cycle and begin division.
Oncogenes can be grouped into five classes based on the nature of their protein products: (1) altered peptide hormones, (2) altered cell receptors, (3) altered G-proteins involved in signal transduction, (4) altered protein kinases, and (5) altered DNA regulatory proteins (transcription factors). A genetic locus on human chromosome 17 is usually associated with colorectal cancer; most of these cancer cells lose one copy of the gene and the other copy has a single base pair mutation. Cancers like this that are associated with the absence of at least one normal gene copy are hypothesized to develop because the normal gene encodes a tumor suppression factor.
EXAMPLE 11.12 The Jun and Fos transcription factors work together to activate transcription of genes that promote cell cycle progression. V-Jun and v-Fos (v stands for viral oncogene) contain deletions and point mutations that make them insensitive to control signals that would deregulate their activities. Thus, these dominant mutations result in constant activation of cell cycle genes. Even if one wild-type copy of the gene is present inside the cell (i.e. c-Jun; c stands for cellular), the unresponsive v-Jun protein will still act in a deregulated manner.
EXAMPLE 11.13 One of the first tumor suppressor genes found is the RB, or retinoblastoma, gene. Retinoblastoma is a cancer of the retina that usually occurs in early childhood. Normal individuals have two wildtype copies of the RB gene on chromosome 13. Individuals that are homozygous for mutations in both RB genes develop cancer. Heterozygous individuals are carriers and are predisposed to cancer if their wild-type copy becomes mutated or lost through a somatic event. The protein encoded by the RB gene is involved in preventing cells from entering the G1/S transition of the cell cycle, keeping them from dividing. When normal RB function is lost, cell division occurs inappropriately, leading to cancer.
Studying Cancer in Vitro
Cells can be grown in vitro using culture techniques referred to as cell culture or tissue culture. Fibroblast cells (responsible for the formation of extracellular fibers such as collagen in connective tissue) are easy to grow in tissue culture. After being placed onto a treated plastic flat-bottomed vial containing a nutrient-rich medium, the cells settle and attach to the bottom of the container and begin to grow. This is called a primary culture. The cells may divide a few times, but they eventually reach a crisis period in which most of them die. However, a few cells may start to grow again, producing an established cell line. Cells of an established line have become immortalized and can continue to divide indefinitely if given fresh nutrients and removal of waste products. However, if they are not continually subcultured, most of the cells stop growing when they have formed a confluent monolayer on the bottom of the container. Their growth is arrested by contact inhibition or density dependent growth. If forced to grow for many generations at high density, or if treated with carcinogens, some of the cells undergo neoplastic transformation and lose contact inhibition. Such transformed cells are thought to resemble or be identical to a tumorigenic condition in vivo. Growth of transformed cells causes them to break out of a cultured monolayer and pile up on each other, forming a focus (foci, plural). Transformed cells can often be grown indefinitely in culture and have several other important properties that distinguish them from normal cells:
- They can grow in cell suspension; they no longer require surface contact for growth and may lose their affinity for attachment to substrates. In vivo, this property fosters metastasis.
- They require less supplementation in the nutrient medium.
- They have disorganized microfilaments (part of the cytoskeleton), and therefore have a tendency to take on a spherical shape.
- They may concentrate certain molecules to high levels.
- Tumor antigens may appear on the cell surface.
- They often form tumors when injected into an animal of the same species from which they were derived.
- Their chromosome number usually exceeds the normal diploid number (aneuploidy).
- If neoplastically transformed by either a DNA or RNA virus, the cell always contains integrated viral DNA.
One of the most important uses of established cell lines has been in the production ofmonoclonal antibodies by use of the somatic cell hybridization technique. A myeloma is a plasma cell tumor that grows well in vitro. Plasma cells are mature lymphocytes that secrete a single kind of antibody. It is possible to fuse amousemyeloma cell (defective in its ability to make antibodies) with a mouse plasma cell to produce a hybridoma able to multiply indefinitely in cell culture and also able to secrete a single kind of antibody (monospecific). Commonly, the plasma cells are derived from spleens of mice that have been immunized with a specific antigen. If the myeloma cells are mutant with regard to their ability to make the enzyme HGPRT, they cannot grow in HAT medium, but they can grow if fused with normal plasma cells that can make this enzyme. The plasma cells, however, usually grow so poorly in HAT medium that they either die or are rapidly outgrown by the hybrid cells. The hybridoma clones can be assayed for antibodies reactive with the immunizing antigen. Once the desired clones are found, they are frozen for later use or propagated indefinitely in cell culture or by injection into syngeneic mice (genetically identical to the plasma cell source) to produce monoclonal antibody-secreting tumors.
Many different plasma cell clones are usually stimulated to respond to the same antigen, each clone producing an antibody that is reactive to a different component or determinant of the antigen (e.g., to different parts of the same antigenic protein molecule). Even antibodies of different clones that recognize the same antigenic determinant may differ in their antigen-binding strengths and in the degree to which they cross-react with related determinants. The monoclonal antibodies produced by a given hybridoma are identical in all respects and can be economically made in virtually unlimited quantities. They are in great demand for a variety of diagnostic, medical, industrial, and research purposes.
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