Characteristics of Cancer Cells

Every cell undergoes an ordered series of events to grow and divide normally. Changes in the cell cycle may result in transformation or cancer (see VIRUS FILE 16-1). Much of what we now know about the oncogenes involved in cancer is attributed to research on RNA and DNA tumor viruses. Three assays have been developed to determine whether viruses or chemical carcinogens transform cells in culture:

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  Focus-forming assays: Transformed or cancer cells lose contact inhibition and form densely packed cells that pile on top of each other (called foci) instead of forming a monolayer of cells that do not grow on top of each other. Normal cells form a mono-layer of cells that undergo contact inhibition. When neighboring cells contact or “touch” each other, the cells stop dividing, allowing a single or monolayer of cells to form on the bottom of a cell culture dish. Normal cells do not grow on top of each other to form foci.

  
  
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  Soft agarose assays: Transformed cells will be able to divide and form free colonies when suspended in a minimal medium containing methylcellulose or agarose, a semisolid or “soft” medium. Normal cells do not proliferate in soft agarose.

  
  
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  Reduced serum requirement: Many transformed cells can grow in medium containing reduced serum or growth factors. For example, normal NIH 3T3 cells will not grow in medium containing less than 5% fetal bovine serum. If Simian virus 40 (SV-40) is used to transform NIH 3T3 cells, the abnormal cells grow in medium containing 0.5% fetal bovine serum.

The properties of cancer, or transformed, cells in culture are different from normal cells in the body. Some transformed tissue culture cells may form tumors when injected into animals. The characteristics of transformed cells in culture are also similar to characteristics of tumor cells removed from experimental animals or patients.

Some of the phenotypic and genotypic changes characteristic of transformed cells in culture or in vitro are as follows:

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  Cells undergo genetic changes, such as an increase in the number and size of nuclei, resulting in instability. Transformed cells may become polyploid with elevated levels of telomerase that maintain telomere length.

  
  
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  Cells become immortalized (cells divide indefinitely) or have an unlimited life expectancy in culture.

  
  
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  Cells undergo metabolic changes, such as dividing and growing rapidly.

  
  
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  Cells display a lack of contact inhibition. Normal cells stop proliferating when they come into contact with another cell, whereas abnormal or transformed cells continue to divide and pile up on top of each other into foci. The foci originate from the same cell.

  
  
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  Cells display anchorage-independent growth/loss of need for adhesion. When freshly isolated normal cells are suspended in a liquid medium and they come in contact with a suitable solid surface, such as the bottom of a culture dish, they will attach, spread, and proliferate as a monolayer on the surface. In contrast, cells derived from tumors or transformed cells grow without the need to attach to a surface.

  
  
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  Transformed cells can grow independently without the addition of serum or growth factors such as cytokines.

  
  
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  Cells undergo a loss of cell cycle control. Transformed cells fail to stop at cell cycle checkpoints in the cell cycle. The growth of normal cells is restricted by these checkpoints.

  
  
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  Cells may have altered cell surfaces. There will be changes in membrane structure and function. For example, transformed cells display tumor-associated carbohydrate antigens on their surface.

  
  
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  When transformed cells are injected into experimental immune-suppressed animals, such as nude mice, tumors may form at the site of injection. Tumor formation defines malignant transformation (FIGURE 16-3).

The following alterations are observed in cancer cells present in the body (i.e., in vivo):

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  Increased oncogene mRNA expression, because the cellular oncogenes have undergone chromosomal translocations, amplifications, or mutations.

  
  
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  The cells lose tumor suppressor function due to a deletion or mutation in the tumor suppressor gene.

  
  
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  Cellular DNA methylation patterns are altered.

  
  
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  Cells produce increased or unregulated levels of growth factors.

  
  
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  Cells divide uncontrollably.

  

  
  
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  Cells have increased levels of enzymes involved in nucleic acid synthesis and lytic enzymes, such as proteases, collagenases, and glycosidases.

  
  
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  Telomerase activity is reactivated.

  
  
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  Cells can avoid the host immunosurveillance response.

Cancer Is a Multistep Process

Tumors arise from a series of events that lead to greater loss of regulation of cell division. For cancer to occur, the following must happen:

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  The cancer cell must bypass apoptosis (programmed cell death).

  
  
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  The cancer cell circumvents the need for growth signals from neighboring cells.

  
  
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  The cancer cell escapes immunosurveillance.

  
  
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  The cancer cell commands its own blood supply.

  
  
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  The cancer cell may metastasize to another location of the body.

  
  
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  Mutations in cellular tumor suppressor genes may be required for full malignancy to occur.

The association between viruses and human cancers is not causal and is often correlative. Viruses are thought to be cocarcinogens in the development of human tumors.

The Retrovirus Genome

Retroviruses differ from DNA tumor viruses in that their genome consists of single-strand RNA (ssRNA) rather than a double-strand DNA (dsDNA). The ssRNA must be reverse transcribed into dsDNA prior to integration into the host’s chromosome. The retrovirus pol gene that encodes reverse transcriptase performs the conversion of ssRNA into dsDNA. David Baltimore and Howard Temin discovered reverse transcriptases independently. Temin was working on his Ph.D. under Renato Dulbecco at the California Institute of Technology (Cal Tech). In 1963, he showed that Rous sarcoma virus could not infect or replicate in cells in the presence of drugs that inhibited RNA transcription, such as actinomycin D and α-amanitin. This was not unexpected, because it was known that the Rous sarcoma virus genome consisted of ssRNA.

To his surprise, though, Temin discovered that DNA replication inhibitors such as 5-bromodeoxyuridine (BUdR) and cytosine arabinoside inhibited the replication of Rous sarcoma virus. For this reason, Temin proposed that the retrovirus reverse transcribed its ssRNA into dsDNA—an idea that contradicted the contemporary dogma that DNA is transcribed into RNA. Once the ssRNA of the retrovirus is copied into dsDNA, the retroviral DNA is integrated into the host cell chromosome. In 1970, Temin and Baltimore isolated and described reverse transcriptase, an accomplishment for which they shared the Nobel Prize in Physiology or Medicine in 1975.

Retrovirus particles contain two copies of the ssRNA genome. The genomes of most retroviruses consist of three or four genes that are located between unique and repetitive sequences located within their RNA genome. The genomes of replication-competent retroviruses (i.e., a retrovirus with a functional pol gene) are 7–12 kilobases (kb) in length. The main genes are labeled gag, pol, and env (FIGURE 16-4A). Gag is an acronym for “group antigens.” The gag gene encodes matrix and core proteins of the retrovirus that function to protect the viral ssRNA genome from damage. The pol gene encodes a multifunctional protein that has reverse transcriptase, RNase H, helicase, and integrase activities. This multifunctional enzyme carries out the reverse transcription process of converting the viral ssRNA template into dsDNA. The env gene codes for a protein that is embedded within a lipid bilayer that surrounds the nucleoprotein core particle of the retrovirus. These proteins are the “spikes” that bind to host cell receptors. FIGURE 16-4B shows the structure of a retrovirus.

The retroviral genome is flanked at each end by noncoding repetitive sequences called long terminal repeats (LTRs). The LTRs contain repetitive sequences (designated R) and unique sequences (designated U). The sequences will enable the DNA copy of the genome to be inserted into the DNA of the host. The genome can act as an enhancer as well, causing the cellular RNA polymerase to transcribe the DNA copies of the retroviral genome at a rapid rate within the nucleus of the host cell.

Each retroviral genome contains a unique (U5) sequence located at the 5´ end of the genomic RNA. The opposite end of the viral RNA (3´ end) contains a U3 region. The U5 region contains a primer-binding sequence. The U3 region contains promoter-enhancer sequences that control viral RNA transcription from the 5´ LTR. The retrovirus virion contains two copies of +ssRNA with the viral reverse transcriptase and a transfer RNA (tRNA) primer bound to each +ssRNA.

Some retroviruses contain an additional gene, v-onc. It is not an essential gene of the retrovirus because it is unrelated to the strategy of viral replication. The v-onc gene was hijacked from the genome of its host during infection. The v-onc was excised with the retroviral genome during a productive infection. It encodes a protein that is capable of inducing cellular transformation (cancer).

Molecular Mechanisms of How Retroviruses Can Cause Cancer: Proviral Integration

Retroviruses may play a role in converting normal host cells into tumor cells via several different mechanisms. When the retroviral dsDNA is integrated into the host’s genome (FIGURE 16-5), it is called a provirus. The integration occurs randomly into the host cell DNA. The pro-virus may be located within or near a proto-oncogene, thereby altering its expression (the altered gene expressed by the viral promoter is called a c-onc). Cellular proto-oncogenes are involved in signal transduction and cell cycle regulation (TABLE 16-2 and FIGURE 16-6). Therefore, a provirus integration event may disrupt the restraints on normal growth and division of cells, causing tumors to form.

The integration of proviral DNA into the host genome can result in the following:

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  Insertional activation of the expression of a protooncogene when viral promoters or enhancer elements cause abnormal expression of an unaltered proto-oncogene, resulting in uncontrolled growth and division of normal cells. The proto-oncogene may undergo hyperactive expression, or it may be expressed at inappropriate times during the cell cycle, causing growth and cell division at inappropriate times (FIGURE 16-7A).

  
  
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  The integration of proviral DNA that carries a v-onc into the host genome. The v-onc may become transcribed and functionally active, disrupting the cell cycle of the host cell. The v-onc may promote unrestricted growth and division of cells, causing tumors to form (FIGURE 16-7B).

  
  
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  Insertional inactivation of a cellular tumor suppressor gene, resulting in uncontrolled growth and cell division. All cancers involve the inactivation of a tumor suppressor gene in addition to other changes in the host cell DNA that result in unregulated growth and cell division. A list of tumor suppressor genes associated with human cancers is provided in TABLE 16-3.

If carcinogens damage a cellular proto-oncogene, the damage may result in mutations in the promoter or within the gene to cause cellular transformation. If the protooncogene is mutated, the expressed proto-oncogene product is abnormal and may be active within the cell at all times to signal growth and cell division. If the promoter region of a proto-oncogene is mutated, the promoter change may result in increased expression or overexpression of the proto-oncogene mRNA. Subsequently, the translated proto-oncogene product is over-abundant within the cell, causing more cell signaling or cell signaling at inappropriate times, leading to the unregulated growth and cell division. The programmed cell cycle is no longer restricted at a checkpoint (refer to Virus File 16-1 to review the cell cycle and cancer to refresh this concept). If the DNA within the proto-onco-gene is mutated, the expressed mRNA is translated into an abnormal protein that may be active within the cell at all times to signal growth and cell division (FIGURE 16-8).

The damage or mutation of the proto-oncogene that codes for platelet-derived growth factor (PDGF) provides a simplified example of how changes in a protooncogene lead to cellular transformation, or “cancer.” PDGF binds to PDGF receptors located on the surface of neighboring cells for a finite time period, activating a cellular kinase. The activated kinase promotes normal cellular growth through a cell signaling pathway within the cell. If the PDGF gene has been altered through viral infection or carcinogens, the mutated PDGF may bind to the PDGF receptor but is unable to free itself from the PDGF receptor at the appropriate time. In other words, the mutated form of PDGF gets “stuck” on the PDGF receptor, activating the cellular kinase within the cell for an indefinite time period. The cell cycle checkpoint is bypassed as the kinase continues to signal the cell to grow (FIGURE 16-9A). In contrast, a mutated PDGF receptor gene may code for an abnormal PDGF receptor that does not require PDGF for activation. Instead, the mutated form may be active constitutively, driving unregulated cellular growth and division (FIGURE 16-9B).

The integrated provirus often remains quiescent as a silent, persistent infection. The proviral DNA may be transcribed by the cell’s RNA polymerase II into viral messenger RNA (mRNA) that is translated by host cell ribosomes. The viral proteins are packaged along with the viral RNA, and the progeny viruses exit by budding from the host cell surface.

Human Endogenous Retroviruses

Approximately 8% of the human genome contains sequences with similarity to integrated proviral retro-viruses known as human endogenous retroviruses (HERVs). The sequences contain the easily recognized gag, pol, and env genes and LTRs. The retroviral sequences have acquired many mutations over the course of evolutionary time so that, with few exceptions, they are now defective and incapable of producing any functional protein. HERVs have been proposed as etiological cofactors in chronic diseases such as cancer, autoimmune diseases, and neurological diseases such as schizophrenia (see VIRUS FILE 16-2). Despite intense efforts by many groups, little direct evidence has been found to support these claims.

Epstein-Barr Virus

Epstein-Barr virus (EBV) was the first human virus to be directly associated as a cause of cancer in humans. EBV is a herpesvirus that is also referred to as human herpesvirus 4 (HHV-4). All herpesviruses have two modes of infection: a lytic replication cycle and a latent replication cycle. A lytic replication cycle is a productive infection in which infectious virions destroy host cells. With a latent replication cycle, the viral genome persists in its host cell without the production of infectious virions; gene expression is dramatically restricted and the host cells are not destroyed.

EBV is named after Sir Michael A. Epstein (1921–), a British pathologist, and Yvonne Barr (1932–), a British virologist. In 1964, these two scientists were the first to isolate EBV from biopsies of jaw tumors collected by Denis Parsons Burkitt (1911–1993). Burkitt, a surgeon born in Northern Ireland, was working in equatorial Africa in 1956. At the young age of 11, he sustained an injury that resulted in the loss of an eye. Even though his eyesight was compromised, it did not affect his insight and observational skills. His father, James Parsons Burkitt, was a civil engineer and amateur ornithologist. James Burkitt was the first to use ringing or banding of birds in order to map their territories. The birding maps had an impact on Denis Burkitt because he later mapped the distribution of the “African lymphoma” (FIGURE 16-10A).

Denis Burkitt earned his medical degree with a specialty in surgery. He joined the Royal Army Medical Corps in England, serving in World War I. Later, Burkitt was sent to serve in Somalia and Kenya. Years later he was summoned to serve at Mulago Hospital in Uganda.

In 1957, Burkitt saw his first case of multiple jaw tumors in a 5-year-old boy. Shortly afterward, he observed more children with jaw tumors and tumors located at other sites of the body. He was the first to observe and report that all of the children with jaw tumors, regardless of tumors located at other locations in the body, were all suffering from the same disease. His first report, “A Sarcoma Involving the Jaws of African Children” was published in the British Journal of Surgery in 1958.

Burkitt observed and described an unusual lymphoma that was very common in children in that region (Figure 16-10). It became known as Burkitt’s lymphoma, a disease that is very similar to leukemia. It is an aggressive, malignant cancer characterized by a solid tumor composed predominately of aberrant B cells (Figure 16-10). B cells are integral to a normal healthy immune system.

Ninety-five percent of the U.S. population between the ages of 35 and 40 are persistently infected with EBV. EBV infection, which is usually asymptomatic, causes a number of conditions. It usually strikes teens and young adults by causing infectious mononucleosis. EBV causes 85% of mononucleosis cases. EBV is transmitted through the saliva of an infected person; it is often referred to as the “kissing disease.” EBV can also be transmitted while sharing a glass, eating utensils, or a straw with an infected individual. Mononucleosis is not usually a life-threatening illness. Rare complications occur if the spleen becomes enlarged with potential to rupture. The incubation period of EBV is 4–7 weeks. The initial signs of infection are sore throat, swollen glands in the neck, fatigue, lack of appetite, headache, and white patches in the back of the throat.

If 95% of the population in developing countries is infected with EBV, why doesn’t everyone get Burkitt’s lymphoma? Burkitt’s lymphoma seems to happen most often in those with a condition that weakens the immune system, such as chronic malaria or acquired immune deficiency syndrome (Aids). Children in Central Africa often suffer from the aforementioned infections. If the children are infected with EBV, Burkitt’s lymphoma occurs. EBV persistently infects b lymphocytes (b cells), resulting in a latent infection. The B lymphocytes of the immune system produce antibodies. Burkitt’s lymphoma is a solid tumor of B lymphocytes. It affects the jaw and very rapidly spreads to the soft tissues and the parotid glands. Analysis of Burkitt’s lymphoma tumors has found genetic aberrations such as chromosomal translocations involving chromosomes 8 and either 14, 22, or 2. These translocations move the c-myc gene near the immunoglobulin heavy chain or light chain gene, resulting in abnormal expression of the c-myc gene and increased tumorigenicity of the cells. EBV DNA and EBV-specific antigens were detected in the tumors. Infection with EBV induces a lymphoma-like disease in New World primates. In vitro EBV immortalization of B cells further supports the link. The mechanism by which EBV transforms cells is still uncertain. The transforming gene(s) have not been precisely identified. Possible candidates are listed in Table 16-4.

Kaposi’s Sarcoma–Associated Herpesvirus

kaposi’s sarcoma was known as a rare skin cancer before the HIV epidemic. It was first described in 1872 by the Hungarian dermatologist Moritz Kaposi (1837–1902). Today, it is referred to as classic Kaposi’s sarcoma, and is a skin cancer that occurs most often in elderly men, most often of Jewish or Mediterranean European ethnic decent. It affects 10–15 males for every 1 female, with an average age of onset of 50–70 years. Single or multiple lesions are usually located in the lower extremities, especially the ankle and soles of the feet (FIGURE 16-11). The tumors responded well to chemotherapy or radiation treatments.

In 1981, a rapid and disseminated form of Kaposi’s sarcoma in young homosexual or bisexual men was first reported in patients suffering from complications of HIV infection, now known as AIDS. Kaposi’s sarcoma has reached epidemic proportions in parts of Africa and the West. It continues to pose a problem in AIDS patients receiving active antiretroviral therapy (ART) and transplant recipients who must undergo immunosuppressive treatment to prevent organ rejection. The lifetime risk for Kaposi’s sarcoma in homosexual male AIDS patients is 50%.

Patrick Moore at the Columbia School of Public Health and Yuan Chang at Columbia College of Physicians and Surgeons identified Kaposi’s sarcoma– associated herpesvirus (KSHV; also called human herpesvirus 8 [HHV-8]) in 1994 as the infectious cause of Kaposi’s sarcoma. DNA sequences of the HHV-8 genome were detected by polymerase chain reaction (PCR) in biopsies of Kaposi’s sarcoma skin lesions from patients with classic, organ transplant–related, and AIDS-associated Kaposi’s sarcoma. HHV-8 DNA was not detected in skin tissue from patients who did not have Kaposi’s sarcoma.

Less than 3% of HHV-8 infected host cells in Kaposi’s sarcoma lesions display evidence of a lytic viral infection. The mRNAs of the latent herpesvirus genes are found in most Kaposi’s sarcoma tumor cells. The HHV-8 genome contains sequences of v-oncs, such as v-cyclinD2, v-IL6, v-Bcl-2, and a number of other v-oncs potentially implicated in the growth deregulation that may be relevant to its proposed role as a transforming herpesvirus (Table 16-4). Effective ART prevents the development of Kaposi’s sarcoma in HIV patients. Kaposi’s sarcoma has dramatically decreased in the United States, where ART is readily accessible. The risk of Kaposi’s sarcoma is higher in HIV-infected individuals and is the second most common cancer in people with HIV/AIDS in the United States. In sub-Saharan Africa, where HIV and KSHV coinfection is high and ART is limited, Kaposi’s sarcoma is a growing public health problem.

Hepatitis B Virus and Hepatitis C Virus: Hepatocellular Cancer

Of all the hepatitis viruses, only hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis, which can progress to liver cirrhosis and hepatocellular cancer (HCC), or cancer of the liver. HBV and HCV are biologically very different viruses. HBV contains a dsDNA genome that replicates by reverse transcription of a RNA pregenome. HCV is a +ssRNA virus that replicates in the cytoplasm of the cell.

Both HCV and HBV mainly infect hepatocytes of the liver, but HCV also infects B lymphocytes. Despite their different replication cycles and genes, both viruses share common characteristics in the mechanisms of the chronic liver disease they cause and their association with cirrhosis, HCC, and ultimately the need for a liver transplant (FIGURE 16-12). The chromosomes of cells from biopsied HCC tumors of cancer patients infected with HBV usually harbor integrated HBV DNA. HCV contains a +ssRNA genome that does not contain an obvious v-onc and does not integrate into host genomes. The mechanism of HCV oncogenesis is not clear. Recent studies suggest that HCV causes chromosomal instability. HCC tumors in HCV patients have a 5- to 10-fold increase in mutation frequency of several cellular genes, such as the genes that code for the immunoglobulin heavy chain, c-bcl-6, p53, and certain β-catenins (Table 16-4).

The routes of transmission by HBV and HCV are similar. Transmission occurs when blood or body fluids of infected persons enter the body of a person who is not immune. Both are spread when sharing needles with an infected person or from an infected mother to the baby during birth. HBV can be transmitted sexually, too; however, there is no evidence of sexual transmission of HCV among monogamous couples. The rate of progression from chronic hepatitis through cirrhosis to HCC in hepatitis C is dramatically higher than that seen with the progression of HBV-induced cirrhosis to cancer. HCC is usually not detected until it is in an advanced stage. HCC cancer is usually fatal within a year of diagnosis.

HCC is the fifth most common cancer in the world. Vaccines are available to prevent HCV infection. The hepatitis B vaccine is the first vaccine to prevent a cancer. Studies have shown that hepatitis B vaccination programs caused a dramatic reduction in the number of hepatitis B carriers in some communities. For example, a 10-year study (1984–1994) in Taiwan found that hepatitis B vaccination reduced the carrier state in children from 9.8% in 1984 to less than 1.3% in 1994. It is anticipated that this significant decrease will be linked to a lower incidence of HCC in children. Donated blood is screened for the presence of HBV and HCV in both the United States and Canada. Most blood centers in Southeast Asia screen donated blood for HBV. Fewer countries are undertaking HCV screening.

Human Papillomavirus

Human papillomavirus (HPV) infections are common among sexually active adults and adolescents. Genital HPV infection is one of the most prevalent sexually transmitted diseases of the world today. In an alarming study of college-age women from a state university in New Brunswick, New Jersey, 43% converted from HPV negative to HPV positive during the 3-year period of study. High-risk types of HPVs cause cervical cancer. Cervical cancer is a major cause of death among women in developing countries and is the third most common cancer among women worldwide.

Papanicolaou (Pap) smear screening programs have reduced cervical cancer mortalities. The Pap smear, or Pap test, invented by Georgios Nikolaou Papanicolaou (1883–1962), is probably the most widely used medical eponym throughout the world and today (see VIRUS FILE 16-3).

Pap test screening began in the 1940s. Between 1947 and 1984 the mortality rate in the United States due to cervical cancer declined by 70%, a reduction that is directly attributed to early detection and removal of the HPV-infected, premalignant tissue. Routine cervical cytological screening in the United States results in the treatment of at least 750,000 women each year for cellular abnormalities suspected to represent possible precancerous lesions.

Pinpointing the cause of cervical cancer was of interest to epidemiologists and physicians for over 160 years. In 1842, Italian surgeon and amateur epidemiologist D. Rigoni-Stern reported that cancer was about five times higher in Catholic nuns than in other women because of an excess of breast cancer in nuns. He also reported four deaths of nuns from uterine cancer. At the time, cervical cancer was not distinguishable from uterine cancer.

Rigoni-Stern studied the death certificates of 74,184 women who died, and found that 1,288 of the women were nuns. Ironically, the study was gradually embellished as a nun’s tale with invented details. Subsequent authors began reporting that cervical cancer was “rare in nuns and common in prostitutes,” suggesting a connection between intercourse and cervical cancer. The idea that cervical cancer was rare among nuns became dogma and most reports on the epidemiology of cervical cancer mentioned Rigoni-Stern’s study. Subsequent studies followed, but careful review of the literature did not support the dogma that cervical cancer is rare in nuns.

In 1986, Ronald Ostrow and his colleagues reported in Science the detection of papillomavirus DNA in human semen. Ostrow’s report supported the position that sexual transmission of HPV DNA could occur by semen. Over the past 20 years, there has been an explosion of research with focused interest on the specific molecular biology of HPVs associated with genital lesions.

Papillomaviruses Are Traditionally Described as Types

Over 120 papillomavirus types have been completely described. The most intensely studied host is humans, but papillomaviruses have been detected from most mammals and birds. Most papillomaviruses cause benign papillomas, or warts, in the skin (especially the hands, soles of the feet, and genitals) or mucous membranes (FIGURE 16-13). HPV infection occurs when the skin is damaged in some way, providing the virus with a means of entry.

More than 150 HPVs have been identified based on the isolation of complete genomes. Of these, approximately 40 types infect the genital area. A database established based on 30 years of sequencing information gained from the genomes of thousands of papillomavirus isolates was used to generate a classification system for papillomaviruses. HPVs are divided into low-, intermediate-, and high-risk types. High-risk HPV types are likely to be responsible for a high proportion of cancers of the cervix, vulva, vagina, anus, anogenital area, and penis (e.g., types 16 and 18). About 70% of cervical cancer cases worldwide are caused by types 16 and 18. There is a 4- to 20-year latent period between infection and development of cancer. Low-risk HPV types are benign from an oncologist’s point of view. They cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis (e.g., types 6 and 11; see VIRUS FILE 16-4). Intermediate-risk HPV types are used to distinguish HPVs that are frequently found in precancerous lesions but are less often represented in cancers (e.g., types 31, 33, 51, 52, and 83).

Cervical Cancer: Oncogenesis

HPV-16 (50%), HPV-18 (15%), HPV-45 (8%), and HPV-31 (5%) DNA is found in nearly all cervical cancer cells using PCR for detection. The remaining 22% of the samples contain other high-risk HPV types. FIGURE 16-17 illustrates the differences in HPV-16 DNA in benign versus malignant tumors. In Figure 16-17a, the HPV genome is maintained as an independently replicating circular extrachromosomal episome in benign tumors. HPV-16 mRNAs transcribed from the episome contain a destabilizing sequence (5´AUUUA3´). In Figure 16-17b, the HPV-16 genome in cervical cancer cells is integrated into the host chromosomal DNA (purple). The HPV-16 genome is interrupted upstream of the E6/E7 open reading frames (ORFs). The viral mRNAs produced from this DNA do not contain the destabilizing sequence. The integrated E6/E7 early genes are overex-pressed in cancer cells. The E6 and E7 proteins inactivate the products of tumor suppressor gene products p53 and pRb. This, in turn, leads to disruption of the normal cell cycle and unregulated growth and cell division, along with chromosomal abnormalities.

Even though most women with cervical cancer are over 45 years of age when diagnosed, HPV infection and disease pathogenesis are known to begin at the onset of sexual activity. Pap test screening is central to treating cervical cancer. Despite widespread screening in the United States, approximately 4,200 deaths due to invasive cervical carcinoma were reported in 2010. About 35% of invasive cervical cancers and 57% of deaths occur in the United States in women over the age of 55. HPV-16 is implicated in cancers of the oral cavity, oropharynx, and throat (see VIRUS FILE 16-5).

Adenoviruses

Adenoviruses were isolated from the adenoids of children by Rowe and colleagues in 1953. At the time, Rowe was searching for different tissues in which to propagate polioviruses. Soon it was discovered that adenoviruses could be isolated from every species of mammal, bird, and amphibian. It became evident that adeno-viruses could persist in lymphoid tissues of tonsils for many years. Approximately 50–80% of enlarged adenoids and tonsils surgically removed are infected with adenoviruses.

Certain human adenoviruses cause malignant tumors in baby rodents, such as hamsters and mice. Two adenovirus genes, E1A and E1B, are responsible for oncogenic transformation of rodent cell lines. E1A inactivates the tumor suppressor gene product pRb, and E1B inactivates the tumor suppressor protein p53. Despite the potent oncogenic properties of some human adenoviruses in animals and tissue culture cells, the virus had not been linked to any human cancers. Subsequently, it was discovered that adenoviruses cause respiratory tract, gastrointestinal tract, and eye infections, including highly contagious conjunctivitis (“pink eye”), and possibly obesity (see Case Study 4 at the end of the chapter) in humans. Respiratory epidemics of adenovirus are often prevalent on military bases. Adenovirus infections are common in people with compromised immune systems, such as AIDS patients.

By 2010, 56 human adenoviruses had been identified. Most individuals are infected with one or more types of adenoviruses before the age of 15. Direct contact, respiratory droplets, or ingestion spreads adenovirus infections. Most infected persons are asymptomatic. No specific antiviral treatment is available for those individuals experiencing symptoms. In rare cases, ribavirin is used to treat adenovirus infections.

Adenoviruses are 80 nm in diameter and of icosahedral symmetry. The capsid is composed of three different major proteins—hexon, penton base, and a knobbed fiber—in addition to a number of minor proteins (FIGURE 16-19). The viral genome is a linear dsDNA that is approximately 36–38 kilobase (kb) pairs in length for mammalian adenoviruses. The genome contains inverted repeats at its ends. Adenoviruses are a prime candidate as gene therapy vectors because they cause mild diseases in humans and their genome replicates with high efficiency in the nucleus of host cells. Adenoviruses can infect a wide variety of tissues, such as the lung, brain, pancreas, thyroid, and heart, as well as skeletal muscle. Over the past decade, adenoviruses have been genetically manipulated to treat cancers (see Section 16.7), cardiovascular disease, genetic disorders, and eye diseases such as glaucoma.

Glaucoma is a blinding eye disease characterized by abnormally high intraocular fluid pressure of the eye. It can result in a damaged optic disk, hardening of the eyeball, and complete loss of vision. The goal of the glaucoma filtration procedure is to create a new passageway by which aqueous fluid inside the eye can escape, thereby lowering the intraocular pressure. A complication of this surgery is side effect bleb scarring after glaucoma filtrations surgery. Adenovirus-based vectors are potential vehicles as an accompanying therapy to glaucoma filtration surgery. A general schematic of adenovirus therapy is shown in FIGURE 16-20.

Vaccine	Year Approved by FDA	Cocktail of HPV Types	Prevention	Vaccination Recommendation by the CDC
Cervarix	2009a	16, 18	Cervical cancer	Three-dose seriesb; given to females only starting at age 9
Gardasil	2006	6, 11, 16, 18	Cervical cancer Vaginal and vulvar cancers Anal cancer in males and females Genital warts in females and males	Three-dose seriesb; routinely given to males and females 11 or 12 years of age; can be given beginning at age 9
Gardasil-9	2014	6, 11, 16, 18, 31, 33, 45, 52, 58	Cervical cancer Vaginal and vulvar cancers Anal cancer in males and females Genital warts in females and males	Three-dose seriesb; routinely given to males and females 11 or 12 years of age; can be given beginning at age 9 through age 26 years
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