Porth's Essentials of Pathophysiology, 4e

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Neoplasia

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grade. Accordingly, on a scale ranging from grade I to IV, grade I neoplasms are well differentiated and grade IV are poorly differentiated and display marked anaplasia. 2 Genetic Instability and Chromosomal Abnormalities. Most cancer cells exhibit a characteristic called genetic instability that is often considered to be a hallmark of cancer. 3,4 The concept came about after the realization that uncorrected mutations in normal cells are rare due to many cellular mechanisms to prevent them. To account for the high frequency of mutations in cancer cells, it is thought that cancer cells have a genotype that is highly divergent from the genotype of normally transformed cells. Characteristics of genetic instability are alterations in growth regulatory genes and genes involved in cell cycle progression and arrest. Genomic instability most commonly results in gross chromosomal abnormalities. Benign tumors usually have a normal number of chromosomes. By contrast, malig- nant cells often display a feature called aneuploid, in which they have an abnormal number of chromosomes. 2–4 The chromosomes may be structurally abnormal due to insertions, deletions, amplifications, or translocations of parts of their arms (see Chapter 6). They may also display microsatellite instability, which involves short repetitive sequences of DNA, and point mutations. Growth Properties. The characteristics of altered prolif- eration and differentiation are associated with a number of growth and behavioral changes that distinguish cancer cells fromtheir normal counterparts. These include growth factor independence, lack of cell density–dependent inhibition, impaired cohesiveness and adhesion, loss of anchorage dependence, faulty cell-to-cell communication, and an indefinite cell life span or immortality. Cell growth in test tubes or culture dishes is referred to as in vitro cell culture because the first containers used for these cultures were made of glass ( vitrium , mean- ing “glass” in Latin). It is assumed that the in vivo (in the body) growth of tumor cells mimics that of in vitro studies. Most normal cells require a complex growth medium and survive for only a limited time in vitro. In the case of cancer cells, the addition of serum, which is rich in growth factors, is unnecessary for the cancers to proliferate. Some cancer cells produce their own growth factors and secrete them into the culture medium, while others have abnormal receptors or signaling proteins that may inappropriately activate growth-signaling pathways within the cells. Breast cancer cells that do not express estrogen receptors are an example. These cancer cells grow even in the absence of estrogen, which is the normal growth stimulus for breast duct epithelial cells. Normal cells that are grown in culture tend to dis- play a feature called cell density–dependent inhibition, in which they stop dividing after the cell population reaches a particular density. 5 This is sometimes referred to as con- tact inhibition since cells often stop growing when they come into contact with each other. In wound healing, for example, contact inhibition causes fibrous tissue growth to cease at the point where the edges of a wound come together. Malignant cells show no such contact inhibition

and grow rampantly without regard for adjacent tissue. There is also a reduced tendency of cancer cells to stick together (i.e., loss of cohesiveness and adhesiveness ) owing, in part, to a loss of cell surface adhesion molecules. This permits shedding of the tumor’s surface cells; these cells appear in the surrounding body fluids or secretions and often can be detected using cytologic examination. Cancer cells also display a feature called anchorage independence . 5,6 Studies in culture show that normal cells, with the exception of hematopoietic cells, will not grow and proliferate unless they are attached to a solid sur- face such as the extracellular matrix. For some cell types, including epithelial tissue cells, even survival depends on such attachments. If normal epithelial cells become detached, they often undergo a type of apoptosis known as anoikis due to not having a “home.” In contrast to nor- mal cells, cancer cells often survive in microenvironments different from those of the normal cells. They frequently remain viable and multiply without normal attachments to other cells and the extracellular matrix. Another charac- teristic of cancer cells is faulty cell-to-cell communication , a feature that may contribute to the growth and survival of cancer cells. Impaired cell-to-cell communication may interfere with formation of intercellular connections and responsiveness to membrane-derived signals. For exam- ple, changes in gap junction proteins, which enable cyto- plasmic continuity and communication between cells, have been described in some types of cancer. 7 Cancer cells also differ from normal cells by being immortal ; that is, they have an unlimited life span. If nor- mal noncancerous cells are harvested from the body and grown under culture conditions, most cells divide a lim- ited number of times, usually about 50 population dou- blings, then achieve senescence and fail to divide further. In contrast, cancer cells may divide an infinite number of times, and hence achieve immortality. Telomeres are short, repetitive nucleotide sequences at the outermost extremities of chromosome arms (see Chapter 2). Most cancer cells maintain high levels of telomerase, an enzyme that prevents telomere shortening, which keeps telomeres from aging and attaining a critically short length that is associated with cellular replicative senescence. Functional Features. Because of their lack of differen- tiation, cancer cells tend to function on a more primitive level than normal cells, retaining only those functions that are essential for their survival and proliferation. They may also acquire some new features and become quite different from normal cells. For example, many transformed cancer cells revert to earlier stages of gene expression and produce antigens that are immunologi- cally distinct from the antigens that are expressed by cells of the well-differentiated tissue from which the cancer originated. Some cancers may elaborate fetal antigens that are not produced by comparable cells in the adult. Tumor antigens may be clinically useful as markers to indicate the presence, recurrence, or progressive growth of a cancer. Response to treatment can also be evaluated based on an increase or decrease in tumor antigens. Cancers may also engage in the abnormal production of substances that affect body function. For example,

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