Cancer and Genetics Help (page 3)

By — McGraw-Hill Professional
Updated on Aug 23, 2011

Studying Cancer in Vivo

In order to metastasize, a transformed cell must undergo several further changes in vivo. Some cells of a tumor must burrow their way into a blood or a lymphatic vessel and then, at some other location, must reverse the process and burrow out into a tissue again. Basement membranes underlie the epithelial cells from which the common cancers are derived, and these membranes consist of a complex of proteins, including collagen IV, laminin, and fibronectin. They also surround the smooth muscles in blood vessel walls. Metastatic cells must produce new protease enzymes to digest the basement membrane (e.g., type IV collagenase, transin). Solid tumors must recruit a rich network of blood vessels to supply them with nutrients for their growth. The process that stimulates formation of these blood vessels is called angiogenesis. Tumor cells are known to produce angiogenic factors that enhance the growth of blood vessels toward the tumor.To form a newtumor, the replicated metas-tasized cell must regain the ability to clump together. In some tumors this has been attributed to the presence of large amounts of a sugar-binding protein on the surface of the tumor cells. During all of this movement and tumor reestablishment, cancer cells have had to undergo additional mutations that allow them to avoid being destroyed by the immune system (e.g., a mutation might alter the proteins in the cell membrane that normally mark the cell for destruction by the immune system).

Oncogenic Viruses

Some viruses are known to carry oncogenes that trigger neoplastic transformation; they are called oncogenic viruses. Among the vertebrates, about 50 oncogenic viruses have been found to contain DNA and about 150 contain RNA. Several families of DNA viruses contain oncogenic viruses, but among the RNA viruses only some of the retroviruses produce tumors. Retroviruses are so named because they contain an enzyme, reverse transcriptase, that synthesizes DNA from an RNA template. This activity is unusual in that most cells only synthesize DNA from DNA, not RNA. Table 11.3 displays some of the major differences between DNA and RNA oncogenic viruses.

EXAMPLE 11.14 The Rous sarcoma virus (RSV) is one of the best understood retrovirus. Upon entry into a host cell, reverse transcriptase, contained within the RSV virion, produces a double-stranded DNA (dsDNA) from the single-stranded virion RNA. This molecule then circularizes and becomes integrated into the host chromosome as a provirus. Progeny virion RNA is synthesized from the provirus by host-cell RNA polymerase II. The provirus is rarely excised. Its presence does not seem to inhibit cell division, so daughter cells inherit the provirus and continue to produce active virions. In contrast to a lambda phage lysogen, the RSV provirus does not make a repressor, and progeny virions are produced continuously without the necessity of deintegration of the provirus.

Unlike bacterial lysogeny, where all phage genes except the one responsible for repression of lytic functions are silenced, genes of the proretrovirus (viral DNA integrated into the host chromosome) are transcribed to produce proteins, some of which are involved in the induction of cancer, and others of which are involved in replication of viral RNA genomes. The integration of viral dsDNA into a host chromosome is an essential step in the life cycle of all oncogenic viruses. The retroviruses are enveloped (membrane-bound) virions containing a single plus (+) strand RNA genome and an RNA-dependent DNA polymerase called reverse transcriptase. This enzyme synthesizes a minus (_) DNA strand using the viral (+)RNA genomic strand as a template. The same enzyme then degrades the viral RNA and synthesizes a complementary (+)DNAstrand using the (_) DNA strand as a template, thereby forming a dsDNA replicative intermediate. The viral dsDNA is then integrated into a host chromosome in the same manner as DNA oncogenic viruses.

Oncogenic viruses cause cancer by two general mechanisms: (1) insertional inactivation and (2) oncogenes. In insertional mutagenesis, the viral DNA causes a mutation simply by becoming integrated into the host's DNA. Some of these mutations might inactivate cancer-suppressor genes. Alternatively, by inserting near a host gene involved in initiation of the normal cell cycle, the activity of that gene might be stimulated to overproduction of its product (e.g., a growth factor).

Many retroviruses contain oncogenes that are identical or very similar to normal cellular genes involved in control of the cell cycle. It is generally believed that retro-viruses have, in the course of their evolution, acquired their oncogenes from these normal cellular counterparts, the protooncogenes. These protooncogenes may become viral oncogenes by integrating into the viral genome in such a way as to be regulated by a powerful viral promoter, causing overproduction of a normal or near-normal growth factor, and resulting in excessive cell proliferation. Alternatively, some of these retroviral oncogenes code for kinase enzymes that phosphorylate specific amino acids in proteins. Normal host-cell kinases phosphorylate proteins at their serine or threonine residues. Retroviral kinases, however, phosphorylate tyrosine residues. Some host-cell growth factors normally stimulate cell division by causing the phosphorylation of tyrosine in the same proteins activated by retroviral kinases. Other oncogenes code for DNA-binding proteins and growth factor receptors, the overproduction or untimely production of which may lead to uncontrolled cell division.

EXAMPLE 11.15 Rous sarcoma virus (RSV) is a retrovirus containing an oncogene v-src (for virus, sarcomaproducing) that can transform cells. All vertebrates possess DNA sequences similar to v-src, and these are called c-src (cellular origin). The product of v-src is a phosphoprotein (pp) enzyme, namely, phosphokinase, called pp60-v-src [60 = 60; 000 daltons (Da) molecular weight]. Most cellular protein kinases phosphorylate the amino acid serine or threonine, but pp60-v-src is tyrosine-specific. Phosphorylation can activate some proteins and inactivate others. Thus, one kinase may affect several proteins in different ways. The number of such proteins affected by pp-60-v-src and their normal functions in control of cell division are not yet known.

EXAMPLE 11.16 The oncogene v-sis, carried by simian sarcoma virus, encodes a protein similar to the platelet-derived growth factor (PDGF) made by the cellular protooncogene c-sis. It is believed that the excess PDGF produced by the virus overwhelms the normal controls on cell division.

Practice problems for these concepts can be found at:

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