Essay on How Infectious Agents Cause Cancer ? | Types | Diseases | Biology

Read this essay to explore: How Infectious Agents Cause Cancer (With Mechanisms).

Essay # 1. Chronic Infections Trigger the Development of Cancer through Indirect as Well as Direct Mechanisms:

The mechanisms by which infectious agents cause cancer can be subdivided into three broad categories. The first involves agents that increase cancer risk indirectly by interfering with immune function. The most dramatic example in this category is HIV, a virus whose ability to debilitate the immune system predisposes individuals to developing cancers that are actually triggered by other viruses, such as KSHV, EBV, HPV, HBV, and HCV.

The presumed explanation is that the weakened immune system is unable to limit infection by these viruses, leaving them free to infect tissues and foster the development of cancer. A related phenomenon is seen with malarial infec­tions, which depress immune function and thereby increase the likelihood that EBV infections will proceed to Burkitt’s lymphoma.

The second category involves infectious agents that create tissue destruction and chronic inflammation. Pathogens acting in this way include HBV, HCV, H. pylori, and parasitic flatworms. By causing tissue destruction, such pathogens make it necessary for the normal cells of the infected tissue to continually proliferate to replace the cells that have been damaged and destroyed.

Persistent infections also create chronic inflammatory conditions in which cells of the immune system, mainly lymphocytes and macrophages, infiltrate the tissue and attempt to kill the pathogen and repair the tissue damage. Unfortunately, the mechanisms used by the infiltrating immune cells to fight infections often produce mutagenic chemicals, such as oxygen free radicals.

Free radicals possess highly reac­tive, unpaired electrons that trigger various types of DNA damage. This means that proliferation of replacement cells for the injured tissue is taking place under conditions in which DNA damage is likely, thereby increasing the possibility that cancer-causing mutations will arise.

Besides producing free radicals, macrophages release sub­stances that enter the injured cells of the surrounding tissue and increase the activity of a protein called NF- kappa B (NF-κB).

NF-κB turns on the transcription of genes coding for proteins that stimulate cell division and make cells resistant to apoptosis, both of which can con­tribute to unrestrained cell proliferation. The net result is that cells in chronically infected tissues are subjected to conditions that promote persistent cell proliferation as well as the accumulation of mutations, two traits that are central to the development of cancer.

The third mechanism by which infectious agents cause cancer is by directly stimulating the proliferation of infected cells. This tactic is used mainly by viruses, although certain bacteria can also stimulate cell prolifer­ation directly. For example, some strains of H. pylori inject a protein called CagA into epithelial cells that line the inner wall of the stomach.

After entering a cell, CagA binds to and activates a key protein involved in one of the cell’s main pathways for stimulating cell proliferation. Strains of H. pylori that produce CagA are more effective in causing disease than those strains that do not produce CagA.

Many cancer viruses can likewise stimulate cell proliferation directly. Some viruses produce proteins that alter the behavior of a cell’s normal growth signaling pathways, leading to uncontrolled proliferation; other viruses alter the expression of normal cellular genes that code for components of these same growth signaling pathways.

The mechanisms used by viruses to disrupt such pathways illustrate a series of principles that apply not just too viral cancers but to cancers caused by chemicals and radiation as well.

Essay # 2. DNA and RNA Viruses Employ Different Mechanisms for Latently Infecting Cells:

Before addressing the question of how viruses disrupt the control of cell proliferation, we first need to clarify a few basic issues regarding the nature and behavior of viruses. A virus is a tiny particle, too small to be seen with a light microscope, that depends on living cells for its reproduc­tion. Mature virus particles contain a core of nucleic acid (DNA or RNA) surrounded by a protein coat and some­times an outer envelope as well.

After entering a cell, some viruses direct the cell to make multiple copies of the virus’s own components, thereby creating new virus parti­cles that are released from the cell. Infections of this type usually kill the cell in which the virus is replicating or expose the cell to destruction by host immune responses.

An alternative mechanism, used by many cancer viruses, is for a virus to conceal itself inside infected cells in a hidden or latent form in which no new virus particles are produced or released. The mechanism for establishing such latent infections differs between DNA and RNA viruses.

With DNA viruses, entrance of the virus into the cell is usually followed by transcription of its DNA into messenger RNA, which is translated into viral proteins that are involved in establishing and maintaining the latent state. Replication of cellular and viral DNA then ensues, leading to cell division. At this stage, the viral DNA may persist indefinitely as an independently replicating molecule called an episome (Figure 7, pathway ①).

Alter­natively, one or more copies of the viral DNA may become integrated into the host chromosomal DNA; the viral genetic information then becomes a permanent part of the cell’s genetic material and is replicated by the cell as part of its own DNA (Figure 7, pathway ②). Whether the viral DNA is replicated as part of the host chromosome or as an independent episome, no new virus particles are produced or released during a latent infection.

Unlike DNA viruses, RNA viruses cannot insert genes directly into a host cell chromosome because their genes are made of RNA rather than DNA. The mechanism for overcoming this limitation was discovered in 1970 by Howard Temin and David Baltimore, who independently found that some RNA viruses contain an enzyme, called reverse transcriptase that catalyzes the synthesis of DNA using viral RNA as a template.

With the aid of another viral protein, called integrase, the resulting DNA copy of the viral RNA is integrated into the host’s chromosomal DNA and is subsequently replicated along with it (Figure 8). When integrated into a host cell chromosome, such a DNA copy of the genes of an RNA virus is referred to as a provirus. RNA viruses that employ the reverse transcrip­tase pathway to integrate their genetic information into a host cell are called retroviruses.

Essay # 3. Retroviral Oncogenes are Altered Versions of Normal Cellular Genes:

As we have just seen, oncogenic DNA and RNA viruses both possess mechanisms for indefinitely replicating their genes in cells that have been latently infected. The big question, of course, is how do such genes cause cancer? In exploring this question, we will begin by examining the behavior of the RNA retroviruses.

The first cancer gene of any type to be explicitly iden­tified and analyzed was a component of the Rous sarcoma virus, the chicken retrovirus discovered by Peyton Rous in the early 1900s. The Rous virus is a small RNA virus whose genome (its total genetic information) includes only four genes, making it relatively easy to identify the gene that causes cancer (Figure 9).

In the early 1970s, Peter Vogt isolated mutant forms of the Rous virus that had lost the ability to cause cancer but could still infect cells and replicate. Examination of the viral RNA revealed that these mutant viruses had lost a single gene whose presence normally allows the Rous virus to cause sar­comas. The gene was therefore named the v-src gene (“v” for viral and “src” for sarcoma). Genes like v-src, which trigger the development of cancer, are referred to as oncogenes.

Subsequent investigations led to the surprising dis­covery that genes resembling v-src are not unique to cancer viruses. DNA sequences that are very similar to, although not identical with, the Rous v-src gene have been detected in the normal cellular DNA of a wide variety of organisms, including salmon, mice, cows, birds, and humans.

Because the evolutionary divergence of this group of organisms occurred hundreds of millions of years ago, it can be concluded that genes resembling v-src have been conserved for a large part of evolutionary history and therefore must perform an important func­tion in normal cells. To distinguish it from the v-src oncogene of the Rous virus, the normal version of this gene in human cells is called the SRC gene (sometimes preceded by the letter “c” for “cellular”, as in “c-SRC”).

Following the discovery of v-src, dozens of other oncogenes have been identified in different retro­viruses. Like v-src, these oncogenes are altered versions of genes occurring in normal cells. The term proto- oncogene is used to refer to such normal cellular genes that are closely related to oncogenes.

For example, v-src is a viral oncogene and SRC is the corresponding proto- oncogene. Cells contain dozens of different proto-oncogenes, each of which plays an important role in normal cellular activities. However, their close resemblance to oncogenes means that alterations in the structure or expression of proto-oncogenes can convert them into oncogenes.

How do we account for the fact that normal cells contain proto-oncogenes that closely resemble the oncogenes of cancer-causing retroviruses? The most likely explanation, illustrated in Figure 10, is that retroviral oncogenes were derived from normal cellular genes millions of years ago.

According to this theory, the first step in the creation of retroviral oncogenes occurred when ancient retroviruses infected cells and integrated their proviral DNA into host chromosomes adjacent to normal cellular proto-oncogenes.

When the integrated proviral DNA was subsequently transcribed to form new viral RNA molecules, an adjacent proto-oncogene could have been inadvertently copied as well, thereby generating viral RNA molecules containing a normal proto-oncogene alongside the viral genes.

Eventually such a proto-oncogene might undergo a mutation that converts it into an oncogene, which would be useful to the retrovirus because of its ability to stimulate the proliferation of infected cells. Such a hypothetical scenario would explain why present-day retroviruses possess oncogenes that are altered versions of normal cellular genes.

Essay # 4. Retroviral Oncogenes Code for Proteins that Function in Growth Factor Signaling Pathways:

The preceding scenario explains how retroviruses may have come to possess oncogenes that are altered versions of normal cellular genes. But how do these oncogenes cause cancer? An early clue came from studies of the Rous virus and its v-src oncogene, which codes for a protein called v-Src. (By convention, gene names are usually printed in italics and the corresponding protein names are printed without italics, as illustrated in Table 3.)

The v-Src protein, first isolated in the late 1970s, is a protein kinase. Protein kinases are enzymes that regulate the activity of targeted protein molecules by catalyzing their phospho­rylation. In the signaling pathways that control cell proliferation, protein kinases play a prominent role in transmitting signals from one molecule to another.

The v-Src protein kinase is a member of a particular group of protein kinases that are called tyrosine kinases because they phosphorylate the amino acid tyrosine in targeted proteins.

Normal cells possess dozens of their own tyrosine kinases, most of which play roles in the various signaling pathways for controlling cell proliferation and survival. Alterations in the proteins involved in growth factor sig­naling pathways can cause the pathways to become hyperactive, leading to uncontrolled cell proliferation.

One protein involved in such pathways, called Src kinase, is the normal version of the v-Src kinase pro­duced by the Rous virus. When certain growth factors bind to their corresponding receptors on the cell surface, the activated receptors in turn activate the normal Src kinase. The activated Src kinase then phosphorylates and activates other signaling proteins that cause the cell to divide.

In contrast to this regulated behavior of the normal Src kinase, which is inactive until stimulated by an appro­priate signal from a growth factor receptor, the v-Src kinase produced by the Rous virus is constitutively active, which means that it remains active whether there is an appropriate signal or not.

So when the Rous virus infects a cell, it produces v-Src tyrosine kinase molecules that persistently catalyze the phosphorylation of target proteins that activate cell proliferation. This Rous v-Src kinase is the first example we have encountered of an oncoprotein—that is, a protein whose activity contributes to the development of cancer.

Subsequent to the discovery of the Rous v-Src kinase, the oncoproteins produced by dozens of other viral onco­genes have been identified as well. Some of these oncoproteins are also tyrosine kinases, whereas others are abnormal versions of growth factors, receptors, or other proteins involved in growth signaling pathways.

The unifying principle to emerge from these discoveries is that many oncoproteins stimulate cell proliferation by functioning as unregulated, hyperactive versions of proteins that are normally used by cells for stimulating cell proliferation.

Essay # 5. Insertional Mutagenesis Allows Viruses with No Oncogenes to Cause Cancer by Activating Cellular Proto-Oncogenes:

Oncogenic retroviruses can be subdivided into two classes based on how quickly and efficiently they trigger cancer in animals. One group consists of acutely transforming retroviruses that cause animals to develop tumors rapidly, often within days of injection. The Rous sarcoma virus is a member of this first group.

The second group consists of slow-acting retroviruses that require months or years to induce cancer. In terms of genetic makeup, the main feature distinguishing the two groups of viruses is that acutely transforming retroviruses possess oncogenes and slow-acting retroviruses do not.

If slow-acting viruses lack oncogenes, how do they cause cancer? The answer is based not on the action of any viral gene but rather on the ability of retroviruses to alter the expression of normal cellular genes. Retroviruses use reverse transcriptase to make a DNA copy of their viral RNA, and the DNA copy is then inserted into the host chromosomal DNA.

The impact of the integrated viral DNA depends on where it is located. Insertion at some chromosomal locations causes no apparent problems, whereas inser­tion at other sites alters the expression of nearby host genes. This phenomenon, in which the integration of viral DNA into a host chromosome activates or dis­rupts a normal cellular gene, is known as insertional mutagenesis.

One of the first examples of insertional mutagenesis to be discovered involved a chicken retrovirus called the avian leukosis virus (ALV). When ALV infects cells, it inserts its proviral DNA at a variety of different locations in the host chromosomal DNA.

Cancer only arises, however, when ALV happens to insert itself near a cellular gene called the MYC gene (Figure 11, top). Like SRC, the MYC gene is a proto-oncogene and thus has the potential to be converted into an oncogene. When ALV integration occurs near the MYC gene, the integrated viral DNA increases the rate at which the MYC gene is transcribed.

Increased transcription in turn leads to overproduction of Myc, the protein encoded by the MYC gene. The Myc protein then carries out its normal function, which is to stimulate the transcription of genes required for cell pro­liferation. There is nothing abnormal about the Myc protein in this particular situation, but its overproduction leads to an excessive stimulation of cell proliferation.

How does the integration of viral DNA into a host chromosome cause the transcription of neighboring genes to be activated? The key lies in special sequences called long terminal repeats (LTRs), which are located at both ends of the genome of retroviruses (see Figure 9). LTRs serve two functions for a retrovirus.

First, each LTR is bounded at both ends by short repeated sequences that play a role in the mechanism by which proviral DNA is inserted into the host chromosomal DNA. Second, LTRs contain sequences that promote transcription of the adjacent viral genes. LTRs are so efficient at this task, however, that they also activate the transcription of neighboring cellular genes that lie near the inserted viral genes.

So if a retrovirus happens to randomly insert its genes near a proto-oncogene, the LTRs may stimulate transcription of the proto-oncogene and trigger overpro­duction of a normal cellular protein that contributes to cancer development.

Essay # 6. Abnormalities Involving the Myc Protein Arise through Several Mechanisms in Viral Cancers:

The preceding mechanism involving the avian leukosis virus is only one of several situations in which the Myc protein has been implicated in the development of cancer. Another example involves the avian myelocytomatosis virus, a retrovirus that also causes cancer in chickens.

Unlike the avian leukosis virus, which possesses no onco­gene but instead enhances expression of a cell’s own MYC gene, the avian myelocytomatosis virus does possess an oncogene and this oncogene codes for an abnormal version of the Myc protein.

Because of its viral origin, the oncogene is called v-myc to distinguish it from the normal host cell MYC gene. In each case, a retro­virus possesses an oncogene that is an altered version of a normal cellular proto-oncogene.

The behavior of the avian leukosis and avian myelocytomatosis viruses illustrates the principle that oncogenic retroviruses can alter production of the Myc protein in two fundamentally different ways:

(1) A virus may disrupt the regulation of a cell’s own MYC gene by integrating proviral DNA in its vicinity, thereby leading to overproduction of the Myc protein by insertional mutagenesis; or

(2) A virus may introduce its own v-myc oncogene coding for an abnormal Myc protein (see Figure 11, bottom).

In the first case, cells produce too much normal Myc protein; in the second case, cells produce an additional, abnormal version of the Myc protein encoded by a viral gene, and this abnormal protein is hyperactive. In both cases, excessive activity of the Myc protein disrupts cell signaling mechanisms that control cell proliferation and survival.

Yet another way in which abnormalities involving the Myc protein arise in virally induced cancers is illustrated by Burkitt’s lymphoma. Burkitt’s lymphoma is associated with infection by the Epstein-Barr virus (EBV), which is a DNA virus rather than an RNA virus like the ones we have been discussing.

Most people infected with EBV do not develop lymphoma, indicating that other factors in addition to EBV are required. One such factor is disruption of immune function (as occurs with malaria or HIV infection), which permits the unchecked proliferation of EBV-infected cells.

Another event must also occur before Burkitt’s lym­phoma will arise. This additional step is a chromosomal translocation involving chromosome 8, the chromosome where the MYC gene normally resides. In the most common translocation, a piece of chromosome 8 con­taining the MYC gene is translocated to chromosome 14, thereby bringing the normal MYC gene into close prox­imity to genes on chromosome 14 that code for antibody molecules (Figure 12).

These antibody genes are highly active in the class of lymphocytes that give rise to Burkitt’s lymphoma because antibodies account for roughly half of the total protein produced by such cells. Moving the MYC gene so close to the highly active antibody genes causes the MYC gene to also become activated, thereby leading to an overproduction of Myc protein that in turn stimulates cell proliferation.

The mechanism responsible for the chromosome 8 to chromosome 14 translocation is not well understood; it may simply be a random occurrence that is more likely to take place in EBV-infected cells because they are constantly proliferating. If this particular translocation happens to occur by chance in just a single cell, the resulting overproduction of the Myc protein would further enhance proliferation of the affected cell and its progression toward malignancy.

Although we have focused our attention on examples involving viruses, it should be pointed out that abnor­malities involving MYC genes and the proteins they produce are not restricted to viral cancers. Mutations in the MYC gene triggered by other mechanisms—for example, mutagenic chemicals, radiation, or spontaneous replication errors—occur in many cancers that are not caused by viruses.

Essay # 7. Several Oncogenic DNA Viruses Produce Oncoproteins that Interfere with p53 and Rb Function:

The Epstein-Barr virus, whose role in Burkitt’s lymphoma we have been discussing, is just one of several kinds of DNA viruses associated with human or animal cancers. Unlike retroviruses, these DNA viruses do not possess oncogenes that are related to normal cellular genes (proto-oncogenes).

Instead, the oncogenes found in DNA cancer viruses are integral parts of the viral genome that facilitate viral replication by disrupting key cellular control mechanisms. At the same time, these viral genes may end up activating the persistent proliferation of the cells they have infected; thereby creating conditions that can lead to cancer.

A good example is provided by the human papillo­mavirus (HPV), a DNA virus whose association with cervical cancer. HPV contains oncogenes called E6 and E7, which produce proteins that disrupt the activity of two key cellular mole­cules: the p53 protein and the Rb protein.

As you may recall, the p53 protein is a central component of the pathway that halts progression through the cell cycle or triggers cell death in cells that have sustained DNA damage. As a result, cells with damaged DNA are prevented from proliferating and passing the damage on to suc­ceeding generations of cells.

The E6 oncogene of HPV circumvents this protective mechanism by producing the E6 oncoprotein, which binds to the p53 protein and pro­motes its destruction (Figure 13). In the absence of p53, HPV-infected cells that incur DNA damage fail to trigger apoptosis by the p53 pathway and are free to proliferate despite numerous mutations.

The Rb protein, which is also targeted by HPV, controls cell proliferation by inhibiting progression through the G1 restriction point in cells that have not been stimulated by an appropriate growth factor. In cells infected with HPV, the virally produced E7 oncoprotein binds to the Rb protein and blocks its function. Under such conditions, the Rb protein cannot restrain passage through the restriction point and cell proliferation pro­ceeds unchecked, even in the absence of growth factors.

So in cells infected with HPV, control of cell proliferation is disrupted by the E7 oncoprotein and the survival of mutant cells is promoted by the E6 oncoprotein, both of which contribute to the development of cancer.

HPV is only one of several DNA viruses that function in this way. The SV40 virus, for example, produces a single protein called the large T antigen that accomplishes both tasks, binding to and incapacitating both the p53 protein and the Rb protein.

Although oncogenes coding for proteins that interfere with Rb and p53 play a central role for these viruses, the mere presence of such genes is not necessarily sufficient to cause cancer. The behavior of HPV is an interesting case in point. Only a small number of the more than 100 different types of HPV cause cervical cancer, yet all the known types of HPV have E6 and E7 oncogenes.

So why are only some forms of HPV carcino­genic? The answer appears to be related not to the presence or absence of the E6 and E7 oncogenes, but to how these oncogenes are expressed in infected cells. When non- carcinogenic forms of HPV infect a cell, the viral DNA is maintained in the cell nucleus as a separate, independently replicating episome.

In contrast, the viral DNA of carcino­genic forms of HPV, such as HPV 16 and 18, integrate their DNA into a host cell chromosome, placing it in a new envi­ronment that alters the way in which the viral genes are expressed (Figure 14).

The net result is the production of slightly different forms of the viral messenger RNAs coding for the E6 and E7 oncoproteins. These altered RNAs are more stable than the RNAs produced by the nonintegrated form of the virus, resulting in the production of larger quantities of the E6 and E7 oncoproteins.

Essay # 8. The Ability of Viruses to Cause Cancer has Created Problems for the Field of Gene Therapy:

We have now seen that viruses can cause cancer through a variety of different mechanisms. As a result, viruses with the potential to cause cancer are not always easy to recognize. An example of the kind of problems this limitation can impose has occurred in the field of gene therapy, which involves treating genetic diseases by inserting normal copies of genes into the cells of people who have inherited defective, disease-causing genes.

One type of gene therapy uses specially modified viruses to ferry copies of normal genes into cells possessing defec­tive genes. To prevent potentially dangerous infections, the viruses are first modified to remove most of their own genes. A normal copy of the gene to be corrected in the target cells is then inserted into the modified virus, and the virus is used either to infect a patient directly or to infect cells isolated from the patient.

One of the first apparent successes of gene therapy was observed in children suffering from a debilitating immune disorder called severe combined immunodeficiency (SCID). The immune system does not develop properly in babies who inherit one of the defective genes responsible for SCID, leaving children fatally vulnerable to what would otherwise be routine infections, such as cold sores or chicken pox.

Children who inherit the disease are some­times referred to as “bubble babies” because they may be forced to live inside a sterile plastic bubble to avoid threats to their debilitated immune systems.

In 2000, a team of researchers led by French pedia­trician Alain Fischer reported dramatic success in using gene therapy to treat children with SCID. These studies employed a specially modified retrovirus that is espe­cially efficient at transferring genes into human cells and integrating them into human chromosomes.

The retrovirus, with the correct replacement gene inserted, was used to infect lymphocytes obtained from a small number of SCID patients, and the lymphocytes were then injected back into the bloodstream. The resulting improvement in immune function was so dramatic that, for the first time, some children were able to leave the protective isolation “bubble” that had been used to shield them from infections.

It was therefore a great disappointment when two of the ten children treated in the initial study developed leukemia a few years later. Examination of their cancer cells revealed that the retrovirus had integrated itself into a chromosome near a normal gene called LMO2, whose abnormal expression is known to be associated with certain forms of leukemia.

Apparently, the retrovirus had triggered an insertional mutagenesis event by integrating in a place where it could activate the LMO2 gene. Integra­tion at this particular site occurs in no more than 1-in-50,000 treated lymphocytes, but because millions of lymphocytes were injected back into each patient, cells exhibiting viral insertion near LMO2 were likely to be numerous. One such insertion event, leading to uncon­trolled proliferation of a single affected cell, might be all it takes to initiate the development of cancer.

This outcome was an unexpected setback for the field of gene therapy because the retrovirus had no oncogene or other feature that would have allowed scientists to predict its significant cancer risk.

One should not, of course, forget that these studies also provided one of the first signs of hope that gene therapy might be able to correct gene defects in children with life-threatening genetic diseases. Nonetheless, the associated cancer risks need to be better understood before further progress can be made.