Cervical cancer was formerly the second most common cancer killer of women worldwide. Following widespread adoption of Papanicolau cytologic screening (Pap test) for cervical cancer in the 1950s, this began to change. Today, advanced cervical cancer is rare in screened populations. Although an uncommon disease in developed nations, internationally about 500,000 women annually are diagnosed with cervical cancer, and about half of those women will die of their disease. In global terms, this ranks second only to breast cancer as a cause of cancer-specific mortality. Over the past three decades the scientific community has witnessed spectacular advances in the understanding of the underlying pathophysiology of cervical cancer, with the most profound discovery being in 1983 of the identification of the human papillomavirus (HPV) within cervical cancer (a discovery that earned Harold Zur-Hausen, M.D the Nobel prize for Medicine and Physiology in 2008). A viral etiology for cervical cancer implied that it may be possible to eradicate cervical cancer through vaccination. This promise was partially fulfilled in 2006 when the United States Food and Drug Administration approved an HPV vaccine for the prevention of HPV-induced cervical dysplasia and/or cancer. These advances, profound though they are, have yet to eradicate cervical cancer. Furthermore, due to the pervasiveness of HPV infection and the timeline of disease progression, it will be a few decades before we will be able to determine the impact preventive practices are having on cancer incidence and prevalence. In addition, those for whom preventative measures are not a solution, including HIV+ individuals as well as women already infected with HR-HPV, await an answer.
Over the past several years, developments in innovative imaging, superior surgical technologies, immunotherapies, and molecular therapies have surfaced, making the eradication of cervical cancer a much more achievable goal than in the past. Several areas of cervical cancer research continue to address the challenges posed by the need for appropriate therapeutic alternatives, and progress is occurring at each level of clinical management ranging from detection to the development of small molecule antiviral leads. Because the field is evolving rapidly in all directions and related disciplines, it is helpful to summarize the status of our growth, and to recognize those pioneering efforts that may ultimately contribute to achieving our goal of eliminating cervical cancer. This review seeks to survey the current understanding of cervical cancer etiology and treatment and to review areas requiring additional progress.
2. Prevention, interception and early detection
Occurring in men and women, HPV infection is most commonly transmitted by sexual contact. According to the National Cancer Institute (NCI), a woman’s risk of acquiring HPV and subsequently developing cervical cancer is increased when the age of sexual debut occurs at a younger age and when the number of lifetime sexual partners is higher . In addition, it has been shown that prevalence rates of infection are consistently higher by 70 percent in sexually experienced, low-income populations of racial and ethnic diversity compared to the general population [5-7]. Also, the risk of HPV infection progressing to cancer depends on lifestyle. For example , at a woman’s first Pap test the risk that HPV16 infection is more likely to progress to carcinoma
UNESCO (United Nations Educational, Scientific, and Cultural Organization) has demonstrated the effectiveness of sex education in the global fight against HIV/AIDs. Although HPV does not currently compare to HIV/AIDs in terms of mortality and global magnitude, the need for HPV awareness has grown tremendously and it is speculated that such a plan may prove useful here as well. An increase in consciousness may decrease sexual risk behaviors if populations at high-risk for contracting HPV were actively targeted for education [16, 17]. However, it should be considered that gender inequalities experienced by women in locations like Sub-Saharan Africa, as reported by the Global Health Corps and UNESCO, may negatively impact these initiatives. Furthermore, the cost of such programs compared to other interventional methods has not been determined. But in general, education can be used as a powerful tool in preventing HPV-mediated diseases such as cervical cancer. Ideally, these programs would emphasize risk-perception in both men and women leading to lifestyle modifications, and a further reduction in the incidence of HPV-mediated carcinoma might be realized.
HPV infections of types other than the four mentioned above are not reliably prevented by vaccination. Also, studies are warranted regarding the vaccine’s long-term effects and how they might impact the occurrence of infections by other HPV types. It has already been noted that quadrivalent and bivalent vaccines may exhibit cross-protection against HPV 31 and other types by 75 to 80 percent . However, concerns are emerging that relate to HPV type-replacement. Type-replacement is an increased prevalence of other HPV strains that are not included in the vaccines, while vaccine-type HPV prevalence is decreased. It was recently reported that vaccine-type HPV has been reduced in vaccinated and nonvaccinated women, while nonvaccine-type HPV has slightly increased overall . Researchers do not expect type-replacement to occur frequently. However, studies are becoming more attentive to changes in the prevalence of various HPV types, which are expected to surface first within the sexually experienced population. Such discoveries could encourage the research community to continue seeking multivalent solutions to as many HPV types as possible without eliciting additional harmful results. To date, clinical trials have revealed that the most common adverse response to both vaccines are injection site reactions, which occur more frequently in vaccine groups rather than in participants given placebos .
Though most industrialized countries, like Great Britain, have already implemented structured HPV immunization programs, well-functioning programs geared towards adults and young adolescents have yet to be seen in many developing countries. However, there are globally funded systems with strong infrastructure that support the immunization of infants in developing countries . This anomaly is due to several challenges, which include the cost of the vaccines, though the biological, economical, and psychological disease burdens of HPV have also been considered [25, 26]. Therefore, it is no surprise that less developed countries have not made HPV vaccination programs a priority while other issues compete for the same limited governmental resources. The most apparent considerations regarding vaccine distribution in these countries relate to healthcare infrastructure, which can directly affect a country’s ability to establish and maintain immunization programs that target the vaccine’s intended population – adolescents. Other factors of significant importance comprise how to best promote these programs in a way that does not aggravate ethnic/cultural sensitivities and attitudes about vaccination against an STI [27, 28]. This would further include easing parental concerns about what an STI vaccine might imply if perceived as socially acceptable within the targeted age groups. Perhaps if immunization programs were set up in an educational setting, a stronger risk-perception might be instilled, which would encourage the formation of better habits of awareness. In years to come, these types of educational agendas might also improve adherence to the 3-dose regimen over the six-month vaccination period and increase compliance with screening routines throughout a woman’s lifetime .
One clear limitation of the HPV vaccines is their lack of efficacy for those who have already been exposed to the virus types included in the vaccines. Of course, this exposure is directly correlated to increasing age and sexual experience [30, 31]. For those who fall into this group, including older women regardless of vaccination status, it is important that screenings continue as outlined by the American Cancer Society (ACS) guidelines for Early Detection of Cervical Neoplasia and Cancer . Therefore, integrated approaches of prevention and detection are required if efforts against HPV-mediated cervical cancer are to be maximized. Another important consideration for vaccination is the immune status of potential vaccine recipients; the immune system must be intact . The immune system’s ability to clear antigens depends largely on its strength and competence. Thus, immunocompromised women are especially in peril of HR-HPV infection progressing to cancer .
The most common scenarios for compromised immunity are seen in HIV+ individuals and organ transplant beneficiaries. Those infected with HIV have a greater chance of HPV co-infection and progression to invasive cervical cancer as compared to those without HIV [34, 35]. The disparity observed here is most likely due to the immune system’s inability to effectively clear virus among this subset due to decreased immune reactivity to HPV antigen [36, 37]. It was also found that HPV infection is prevalent among those receiving organ transplants , and that the infection increasingly persisted throughout immunosuppressive therapy to moderate graft rejection . Despite these challenges, researchers agree that previous prophylactic HPV vaccination is still beneficial for organ transplant recipients as well as the HPV/HIV co-infected population who receive HPV vaccination before becoming HIV+. In these cases, any future challenges of HPV infection following vaccination would be neutralized by an earlier developed immunity prior to the individual presenting as HIV+. This is based on the premise that the protection conferred against the viral types represented in the vaccine is expected to last for the same time period as in others who are not infected with HIV. However, what remains unclear is whether the vaccine will prove effective for an individual already infected with HIV, or in any immunocompromised state . The current understanding is that humoral immune responses remain relatively intact following HIV infection. However, in such a state of immune weakness, it is unknown whether protection against HPV can be sustained. Overall, individuals who have been vaccinated prior to becoming immune compromised are expected to benefit from vaccination by maintaining immune competency, because new HPV infections from these specific types and the risk of lesions reactivating from an ongoing, latent HPV infection would be reduced. Of course, they, like other individuals, will only be protected from the vaccine-type strains, and it is imperative to note that questions regarding long-term safety in such vulnerable groups remain unanswered [30, 31, 33, 40, 41].
To this end, it is important that innovative therapeutic approaches to improve immunological surveillance and clearance of HPV continue to develop. It is well-documented that cellular immune components contribute directly to natural clearance of the virus in most people. For instance, CD4+ and CD8+ cytotoxic T cells (CTLs) are thought to target HPV 16 early and late proteins, and active HPV-specific CTLs have been identified in patients with existing infections . Furthermore, researchers have found that in response to a vaccine containing E6 and E7 oncoproteins, CD4+ and CD8+ CTLs were stimulated, thus inducing the regression of HPV-mediated vulvar intraepithelial neoplasia (VIN) in 50 percent of subjects . A variety of other immunotherapy investigations are underway and will be discussed in more detail later in the review.
The role of chronic inflammation and its link to radical species production in cancer pathogenesis is widely recognized. If increased levels of oxidative stress and ROS do indeed increase the frequency of integration and cancer, one would predict that antioxidant mechanisms that counteract the generation of radical species could therefore exert chemopreventative and chemotherapeutic effects; such mechanisms have indeed been described [52, 53]. In contrast, other groups are studying ways to therapeutically harness the power of oxidative stress for actions against cancer cells. For example, the antimalarial drug, artemisin, was found to induce apoptosis in cervical cancer cells. The mechanism of action involves artemisin interacting with reduced iron to generate oxidative stress through ROS, as well as the destabilization of mitochondrial oxidative mechanisms [45, 54]. These discoveries merit further research that continues to seek ways of preventing HPV-mediated oncogenesis.
The most utilized and successful of screening methods in lowering cervical cancer incidence rates (by 70 percent) is exfoliative cervicovaginal cytology, or the Pap test. The Pap test satisfies the aforementioned objectives for reducing the occurrence of squamous cervical carcinoma through appropriate screening . Pap tests are recommended for all sexually active women and/or women ages 21 and older. Now, a modified liquid-based version of the Pap smear is available. In a liquid-based Pap test such as Cytoscreen or Thinprep, the cells are first filtered and fixed in preservative. Then the specimen is smeared on a glass slide, which is slightly in contrast to the conventional method of directly smearing a sample onto a microscope slide. Other tests such as visual inspection with acetic acid (VIA) are useful in resource-limited settings. Further modifications of VIA include magnified visual inspection with acetic acid (VIAM) and visual inspection with Lugol’s iodine solution (VILI) . Colposcopy, though considered more diagnostic, also allows a magnified visualization of abnormal cervical cells . Other cervical cancer screening tests may also be applied: pelvic examination – involving internal palpation of the reproductive organs; automated cervical screening techniques – supplemental imaging that reduces false positives from the cytological tests; computer imaging; polar probe – measuring the differences in electrical stimulation between normal and abnormal cervical tissue; laser-induced fluorescence – measuring spectroscopic differences in florescence between normal and diseased cervix; speculoscopy – cervical inspection using acetic acid with chemiluminescent light; and cervicography – photo development while using acetic acid .
Complementing the Pap test is the detection of HPV DNA. The direct testing for HPV DNA is becoming standard in many cervical cancer screening regimens, as its combined use with liquid-based cytology has generated results with even better sensitivity (up to 100 percent) for predicting high-grade cervical dysplasia . HPV DNA is usually obtained from cervical scrapes and/or biopsy specimens, and recent clinical studies continue to assert the unique value of HPV-DNA testing over cytology [59-61]. Nevertheless, only time will tell the extent to which the Pap test will be replaced by the more economically appealing HPV-DNA test. To date, the FDA has approved five HPV-DNA tests: the Hybrid Capture 2 HPV DNA test, the Cervista HPV HR test, the Cervista HPV16/18 test, the Cobas 4800 HPV test, and the Aptima HPV assay. Other commonly used assays not approved by the FDA include PCR and Southern Blot hybridization, the latter being the laboratory gold standard. Some other recent innovative HPV detection methods are complete HPV genotyping, HPV mRNA detection, HPV load quantitation, identifying HPV integration, p16 ELISA, methylation profiles, and the E6 Strip test [62, 63].
Cervical cancer incidence and mortality seem to be on a downward swing in the U.S., primarily due to cytological gynecologic screening through the Pap test. Nevertheless, the global burden of HPV infection remains. Because no single detection method is optimal for every situation, it is essential that novel techniques to identify cervical cancer and HPV infection be continuously developed. Ideally, these new procedures/assays would allow clinicians to easily distinguish between low-risk and high-risk HPV status without causing undue concern in patients with transient infection. However, the cost of cervical cancer screening programs, even in developed countries, may hamper the implementation of these new advances.
3. Current clinical treatmemts
The staging of cervical cancer is based on the physical examination and is established by the International Federation of Gynecology and Obstetrics (FIGO). The World Health Organization reaffirms the FIGO organization of cervical carcinoma progression into four stages (I-IV):
The four main stages are then organized into sub-categories that further describe the extent of growth, adjacent tissue involvement, local organ participation, and metastasis to distal sites through the lymphatic system . Present challenges to the optimal clinical staging of cervical cancer include complications associated with parametrial invasion, tumor location/size variation, and lymph node metastases, but developments in imaging are changing the tide [67, 68]. The ACS asserts that individuals diagnosed with cervical cancer from the early stages through late stage II actually have a survival rate greater than 50 percent. Cancers diagnosed at stage III and IV yield 30 and 15 percent survival rates, respectively. However, survival rates approach 100 percent if the cancer is caught early enough. The tools used in the process of staging and subsequent treatment of cervical cancer are numerous and will be mentioned only as they fit the scope of this review. Therefore, the sections below are not intended to represent a comprehensive discussion of these modalities.
Surgery is immensely valuable for determining lymph node status, which is strongly correlated to survival . The risk of lymph node metastasis is increased by 10 percent if tumor invasion reaches between 3 and 5 mm beyond the primary lesion. If this occurs, the NCI recommends that a modified RH comprising pelvic lymph node dissection be performed even in early disease stages. Furthermore, if metastasis to the lymph nodes or parametria is found, their removal is indicated as well as radiotherapy or chemo radiotherapy post-operatively. Post-surgery radiotherapy is also indicated if the tissue collected during surgery has a positive margin, which alludes to residual cancer and commonly occurs in late stage I. Though it is advisable to use radio and chemotherapies in stage II, some experts also support hysterectomy following these procedures. In summation, surgery yields its most potent benefits in the earlier stages of cervical carcinoma, though this fact can be viewed as a great limitation in the case of advanced disease. Other limitations of surgery include pelvic sepsis and thrombosis as well as vesicovaginal fistulas. However, opting for surgery in the management of cervical cancer may prevent vaginal stenosis, spare ovarian function, and protect local organs from future complications. There is no doubt that surgery is vital in the prospective treatment planning of the patient following operation because it allows the delineation of tumor metastasis . However, surgical options are contingent upon early detection, and thus time will always be one of the most important factors in predicting a prognosis. Fortunately, advances in the field of surgery have given patients better alternatives that are less invasive (i.e. laparoscopic surgery), and these procedures, together with non-invasive therapies, will continue to benefit those for whom preventive measures have failed.
Maximum dose toleration by adjacent tissues such as vaginal tissue is a major limiting factor in all radiotherapy procedures. Therefore, many strategies attempt to radiosensitize the appropriate tissues (
Cisplatin, a platinum-based agent, is the accepted standard of chemotherapy for cervical cancer, and it improves survival in chemoradiation recipients as compared to the use of other chemotherapeutic drugs [90-94]. However, its adequacy in improving survival and quality of life in palliative management has been questioned. Some tumor cells acquire resistance to cisplatin, and so non-platinum chemotherapy or higher doses of cisplatin, in these cases, are indicated [81, 91]. In the cases of cisplatin resistance or disease recurrence, non-platinum-based agents such as topotecan, vinorelbine, irinotecan, paclitaxel, mitomycin c, and ifosfamide are sometimes combined with cisplatin. Topotecan and 5-fluorouracil (5-FU), among other combinations, seem to produce an additive effect with cisplatin to reduce its toxicity, increasing its RR from 20 to 50 percent [90, 91, 95]. Similarly, when paclitaxel is combined with cisplatin, a high RR of 46 percent is reached for late stage IV cervical cancer and is accompanied by decreased hematologic complications. However, a Gynecologic Oncologic group study reported that consistent, weekly schedules of cisplatin alone are less toxic than cisplatin combined with other agents, particularly 5-FU [92, 96]. Sanazol and tirapazamine are relatively new chemotherapeutic agents that specifically target and destroy hypoxic tissue by dissociating into free radicals that cause DNA damage. Therefore, drug selectivity for hypoxic tissue will result in greater cytotoxicity among malignant cervical cells . Multiple-agent regimens may also include the use of antibodies targeting a tumor’s peculiar characteristics. For example, if a particular tumor markedly over-expresses EGFR-1, it would be appropriate to include Cetuximab in treatment, or Bevacizumab in the case of extreme vascularity .
4. Molecular therapies in development
Live, vector-based vaccines, bacterial and viral, can generate very robust cell-mediated and adaptive immune responses, and because of this they are preferred over peptide/protein vaccines. Specifically, bacterial vectors function well when they are packaged with antigen (genes or proteins), thereby alerting antigen-presenting cells (APCs) to initiate an immune response. Though several bacterial vectors have been tested,
In peptide-based vaccines, antigens from HPV are directly administered to elicit a response from dendritic cells (DCs)
In general, protein-based therapeutic vaccines, like peptide-based vaccines, are advantageous for safety and tolerability. Although protein-based vaccines are not restricted by MHC compatibility, they cannot directly stimulate cytotoxic T lymphocytes. Protein vaccine adjuvants that are considered to compensate for this weakness in protein vector therapy include liposome-polycation-DNA and the saponin-based ISCOMATRIX. The ISCOMATRIX is an adjuvant complex consisting of phospholipids and cholesterols, and it causes a rapid innate immune cell response . In general, any strategy that increases antigen uptake by APCs, antigen presentation, or the CTL response is expected to improve the immunogenicity of a protein. One protein-based therapeutic vaccine in clinical trials is TA-CIN. Essentially, TA-CIN is a mixture of L2, E6, and E7 proteins from HPV16. The L2 antigen launches a humoral response, and the E6 and E7 proteins induce T cell responses. However, further investigation revealed that TA-CIN is even more powerful when combined with the TA-HPV vaccine [113-115]. Another strong protein-based vaccine candidate, due to its safety and ability to induce lesion regression in various HPV-related diseases, is HspE7 . HspE7 is a fusion product of HPV16 E7 and the
One advantage of DNA-based vaccination is its capacity to increase immunological memory through constant antigen production. Because the immune response itself is not anti-vector, multiple vaccinations are possible. Moreover, the antigens produced by DNA vaccines can be delivered in a variety of ways, resulting in stimulation of both APCs and T lymphocyte immune defenses [118, 119]. However, DNA vaccines also present the challenge of overcoming low immunogenicity due to limited APC specificity. Therefore, future developments must focus on antigen modifications so as to elicit a stronger DC adaptive immune response. One such strategy increases the number of HPV DNA plasmid transfection events in DCs. These DCs will then present antigen to, and ultimately activate, naive CD4+ and CD8+ lymphocytes . However, researchers still must determine the most efficient and effective way to deliver HPV DNA to DCs. A fairly recent investigation discusses a novel method to administer a dose-driven vaccine by gene gun technology, which forms a DNA-coated stream of gold particles targeting Langerhans cells in the skin . Other studies justify the use of cell membrane permeabilization by electroporation, thereby causing cells to experience an electric shock and maximizing cellular uptake of DNA [121, 122].
Electroporation also leads to inflammation and cytokine recruitment, thus enhancing the immune environment. Additionally, electroporation was found to be particularly effective against E7-expressing tumors. The VGX-3100 plasmid DNA vaccine, targeting E6 and E7 antigens of HPV16 and 18, seemed to have great efficacy when it was combined with electroporation administration . Furthermore, clinical trials attest to the value of this particular method of treatment delivery in CIN 2 and 3 lesions. Strategies that increase transfection efficiency are continuously being sought through experimentation with diverse routes of vaccine administration, such as intramuscular
Another strategy to strengthen DNA-based vaccines focuses on improving DC antigen processing. Those cells that have become transfected with HPV DNA material may be prompted to generate a more potent immune response through codon optimization or demethylation techniques that will increase gene translation efficiency . These methods work to improve antigen translation and expression in cells with HPV DNA. Additionally, DNA vaccination with the MHC class I chaperone molecule, calreticulin, was shown to increase the CD8+ immune response, thereby leading to an antitumor effect . It is also possible to improve antigen processing through the MHC class II pathway. For instance, the E7/LAMP-1 vaccine allows antigen to be further sorted in endosomal and lysosomal compartments, thus priming CD4+ and CD8+ lymphocytes for a greater response as compared to the administration of E7 alone . Substitution of the MHC class II peptide, CLIP (Class II-associated peptide), for the PADRE peptide in the invariant chain is a promising strategy to not only increase antigen presentation, but also to secrete cytokines that stimulate T cell proliferation, thus resulting in greater CD4+ lymphocyte activity [131, 132]. Other methods of improving antigen presentation include cross-presentation by extracellular proteins like HSP 70, up-regulation of MHC II expression on the surface of DCs, and single chain trimer technology (SCT). SCT involves the fusion of HPV antigen to the MHC class I molecule, beta-2 microglobulin, resulting in the appropriate recognition of antigen and action against an E6-expressing tumor [133, 134].
RNA replicon-based vaccines have some advantages over DNA vaccines: 1) they are less likely to integrate into the host genome, thus decreasing the risk of cell transformation and 2) they can potentially generate more protein than can DNA methods. Of course, RNA replicon-based vaccines may be introduced into the host as DNA. From here, the cell can then transcribe the DNA molecule into RNA, but without the structural genes needed to construct viral particles. Therefore, no antibodies are produced against viral immunologic molecules and administration can be repeated. One significant limitation of using replicons is that RNA is inherently unstable. However, the use of a DNA-launched RNA replicon could surmount this difficulty, and concerns of gene integration could be addressed by designing the DNA to self-destruct following gene expression. Because immunologic cells undergo apoptosis in this process, it is necessary to fuse the HPV antigen to an anti-apoptotic protein, otherwise DC numbers will be drastically reduced [100, 135, 136]. The Kunjin flavivirus has the potential to accomplish the same goal by delivering the desired antigens into cells without immediately inducing apoptosis, thus prolonging the window of time for antigen presentation by transfected cells and improving overall immunogenicity [137-139].
Dendritic cell-based vaccines can be prepared in several ways: by introducing exogenous HPV antigen via endocytosis in to DCs; by infusing DCs with E6/E7 DNA or RNA through electroporation; or, the antigen may be packaged together with liposomes or nanoparticles to be delivered into DCs . DC interactions with T cells and the subsequent perpetuation of the immune signal are essential features that determine whether an organism will demonstrate a strong immune response, or whether it will exhibit immune tolerance (e.g. if the DCs are immature) [141, 142]. Essentially, DCs activate T cells and T cells, in turn, mediate DC apoptosis. Therefore, it has been proposed that prolonging DC survival may strengthen and lengthen the initial T cell stimulation . However, because the idea of combining HPV vaccines with anti-apoptotic proteins has not gained much popularity due to the possibility of cellular transformation, other approaches such as co-administering vaccines with siRNAs targeting pro-apoptotic proteins are gaining traction. Designing shRNAs directed at FasL produced by DCs to promote T cell apoptosis, for example, could increase the number of T cells stimulated . DC activation can also be prolonged by deactivating the negative regulation of cytokine signaling through SOCS-1, which acts on the Jak-Stat pathway [132, 145, 146].
Because tumor cell-based vaccines have shown promise in malignancies like melanoma, colon and prostate cancers, many subscribe to this paradigm as the key to solving the cervical carcinoma dilemma. The idea of manipulating tumor cells into becoming more discernible by the immune system is based on their expression of immunomodulatory cytokines like IL-2 and IL-12 . Other studies have found that engineering tumor cells to secrete pro-immune cytokines such as GM-CSF produces antitumor immunity as well . The advantage of using tumor cell-based vaccines is that multiple antigens can be targeted on the surface of a tumor, thus increasing the chance that a single cell or group of cells expressing those antigens will be eliminated by the immune system. As can be expected, such an individualized treatment is costly and may border on the impractical as compared to other recent advances in the field of cervical cancer vaccination. Furthermore, patients who qualify for tumor cell-based vaccination would be at greater risk in the receipt of new cancer cells than if they were to employ a treatment plan composed of existing therapies .
Of course, every approach has its advantages and disadvantages, but combining several therapeutic vaccines into a single regimen may offer synergy and thus strengthen treatment efficacy. For example, one preclinical study tested a prime-boost vaccination model. The immune system was first primed with a DNA vaccine consisting of HPV16 E7 and LAMP-1 (Sig/E7/LAMP-1). Then, a booster dose of Sig/E7/LAMP-1 was given again to maintain and increase the T-cell response over a longer period . Because several prime-boost studies have yielded continuous positive results in safety and efficacy, we can expect to see similar combinatory therapeutic trials in the future.
Tristetrapolin (TTP) is an RNA-binding protein with anti-cancer properties, and yields its effects by binding to AU rich regions of mRNA and promoting their destruction. These AU-rich elements (AREs) of mRNA, located in the untranslated region of the strand, are naturally involved in regulating cellular growth and inflammation
Studies have revealed that certain host proteins are co-opted by the virus and used to carry out viral functions. For instance, the bromodomain protein, Brd4, which normally serves as a regulator of cell growth and transcription, has been implicated in the tethering of bovine papillomavirus (BPV) episomes to chromosomes in dividing cells [164, 165]. Also, it was recently published that Brd4 not only binds to the HPV regulatory protein, E2, aiding in many of its functions, but also stabilizes it [166, 167]. Although the ways in which Brd4 can interact with the bovine and human papillomaviruses may differ, the concern that Brd4 may play a key role in viral replication appears to be substantiated. Regarding PV E2, research has indicated that its N-terminal transactivation domain is quite conserved among the papillomaviruses . Thus, many of the properties of the PV E2 protein are likely to be shared between many PVs . Origin-specific viral DNA replication is overseen by E2 once the viral helicase, E1, has been loaded successfully onto the origin of replication by E2. E2 also represses the expression of E6/E7 oncoproteins at the transcriptional level, in addition to performing other regulatory tasks. Therefore, it could be quite detrimental to the intracellular establishment of the virus, its subsequent replication and cellular transformation if the interactions between E2 and its cellular partners could be targeted. For example, while Brd4 is bound to E2, E2 is unable to engage P-TEFB, a transcription elongation factor, and this affects the expression of downstream genes such as E6 and E7 from the integrated viral genome . Future studies are expected to provide more conclusive data regarding P-TEFB, the roles of Brd4, and their association with HPV proteins. But as a key regulatory protein, the importance of E2 on HPV viability and replication makes it a prime target for intervention.
E1 is the only enzymatic product of the viral genome, coding for an ATPase, and is thus an appealing target for molecular intervention. Indeed, if E1’s binding and helicase properties could be blocked, DNA replication would be halted. Inevitably, impeding this process would also thwart the hijacking of cellular replication machinery for viral genome multiplication. Because the virus uses cellular replication factors derived from the host, current antiviral agents that block viral proteases and polymerases are ineffective in opposing HPV. DNA helicase unwinding is powered by the energy provided through ATP hydrolysis
Small molecular inhibitors called indandiones are recognized as the first class of molecules to block HPV DNA replication by interrupting E1-E2 binding. The presence of indandiones induces conformational changes in E2, forming a deep binding pocket through which the small molecule modifies protein activity . The success of preliminary trials attests to the great potential and need of inhibitors intended for binding pockets. Repaglinides operate similarly to indandiones in disrupting E1-E2 binding, though their effect is reversible, and they are reported to occupy a larger area of the binding pocket than do their indandione counterparts. One limitation for these classes of compounds is the poor binding frequently observed between small molecules and a large protein interface. However, these studies have demonstrated that designing small molecules to target large protein interfaces might actually be necessary in order to disclose pockets thought not to exist, or to create new ones. Another factor that must be considered is the fact that viral integration into the host genome frequently leads to loss of E1/E2 gene expression, meaning that established cancers are likely to have lost the molecules targeted by inhibitors of E1 and/or E2, thereby limiting their usefulness [174, 175].
In contrast, E6 and E7 are frequently over-expressed in established cancers, making these two proteins quite attractive as targets. E6 and E7 are the zinc finger-containing proteins primarily responsible for the malignant alterations and de-differentiation of keratinocytes observed during cell transformation. These changes occur following integration of the HPV genome into host DNA [163, 176]. During this process, the regulators of viral replication, E1 and E2, are frequently disrupted, allowing over-expression of E6 and E7. HR-HPV types induce cell immortalization and transformation primarily through the over-expression of E6 and/or E7, which are best known for their ability to accelerate the degradation of the p53 and retinoblastoma proteins (pRB), respectively. The E6-mediated loss of p53 function leads to an insensitivity to apoptotic signals as well as to a loss of cell cycle regulation at the G1/S checkpoint in response to DNA damage. E7 contributes to the hyperplasia crisis by accelerating the degradation of pRB and thereby stimulating cells in Interphase to re-enter the cell cycle at S phase [177-179]. Together, over-expression of the E6 and E7 oncoproteins, decrease apoptosis and increase cell division, setting the stage for cancer . Antiviral agents that can partially, if not fully, inhibit E6 and/or E7 functions clearly have the potential to negatively impact the carcinogenic process. One group, for example, proposed such a strategy in their study of the HPV16 E7-antagonizing peptide, Pep-7 . Pep-7 was originally introduced as a short peptide component of the vacuole/lysosomal pathway . However, Pep-7 was later shown not only to reduce the viability of HPV-positive cells
In contrast to E7, which appears to act primarily by increasing the ability of expressing cells to replicate, E6 acts by reducing the ability of expressing cells to undergo apoptosis. Apoptosis is a natural, cell-mediated death response to irreparable DNA damage. One target of E6 is the p53 tumor suppressor, which is degraded following association of E6 with the ubiquitin protein ligase, E6AP. The E6/E6AP complex binds to p53 and initiates its ubiquitination and consequent proteolytic destruction . This means that the downstream targets of p53, which mediate cell cycle arrest and apoptosis, are not activated. Therefore, interference with the E6/E6AP-mediated proteasomal degradation of p53 has been seen as another possible strategy for treatment. The ubiquitination proteasome system (UPS) begins with the ubiquitin activating E1 molecules interacting with E2 conjugating enzymes, followed by catalyzation of the polyubiquitination cascade onto target proteins by E3 enzymes . A subset of E3s, called RING-finger E3s, are a group of ubiquitin ligases that have domains to which ubiquitination substrates bind, and it is thought that by inhibiting this interaction, p53 might be preserved. One prominent p53-related RING-finger ubiquitin ligase is MDM2. MDM2 is normally expressed in a negative feedback manner to regulate p53 levels. Three dominant trains of thought have guided approaches seeking ways in which the negative effects of MDM2 might be neutralized: 1) Blocking activation domains on p53, 2) Increasing nuclear export of p53 so as not to activate MDM2 transcription, and 3) Inhibiting MDM2. Of these, the third approach has received the most attention. In one such study, small molecules were screened and selected based on their MDM2 inhibitory properties, and a class called the Nutlins was discovered. Nutlins competitively bind MDM2 at the same site typically occupied by p53, and structurally interpose themselves between p53 and MDM2 . In contrast, another molecule labeled RITA actually binds to p53 and stabilizes it against degradation by inhibiting p53 from interacting with most of its binding partners, including MDM2 . A more recent addition to the MDM2 inhibitor group is TRIAD1, a RING-finger bearing molecule, that functions similarly to RITA in that it binds p53 (at the C-terminus), and also intercepts ubiquitination triggered by MDM2 .
One well-established inhibitor of the UPS is Bortezomib. Bortezomib targets and reversibly blocks 26S proteasome activity, and has already been FDA-approved for the treatment of multiple myeloma and lymphoma . Though its use has been proposed for the treatment of many diseases, from non-small cell lung cancer to pancreatic cancer, an equivalent and thorough exploration in the context of cervical carcinoma is still needed . This suggestion is solidly founded on the observed sensitization of cervical cancer cells to apoptosis by another protease inhibitor (PI), MG132 . A final set of PIs are those that inhibit the HIV protease. The anti-oncogenic properties of HIV PIs were first noted with respect to the 20S proteasome, and further investigation explicitly demonstrated Lopinavir active against E6-induced p53 degradation. Though Lopinavir also stabilizes p53, it exhibits low potency and virus is not fully cleared. The value of HIV PIs in cervical cancer treatment could be potentiated by its current availability as an antiviral agent, which might expedite the clinical trial process [191-193].
While p53 and the proteins to which it is connected are clearly targets worth exploring, other pro-apoptotic targets could prove just as important in halting the progression of HPV-mediated disease. HPV16 E6 binds to several additional signaling molecules in the intrinsic and extrinsic apoptotic pathways, including Bax, FADD, and procaspase-8, thus blocking their ability to interact with their normal partners and leading to their premature disposal by the proteasome. Not only does HPV16 E6 indirectly affect Bax
5. Final remarks
In summary, the scientific community has witnessed tremendous progress in the recent years towards the goal of eradicating HPV-mediated cervical carcinoma. Of these endeavors, routine Pap testing and the prophylactic vaccines, Gardasil and Cervarix, are particularly noteworthy for their documented and anticipated progress in decreasing the burden of this disease. Improved vaccines are under development, as are better methods for early detection. Additionally, recent discoveries pertaining to the HPV life cycle, viral infection, and immune clearance have provided guidance toward educating the public about the biological and behavioral risk factors linked to cervical cancer. However, awareness among the populations of greatest risk, in both developed and underdeveloped countries, is lacking. Although high-risk individuals may belong to diverse ethnic groups and/or have lower socioeconomic standing, they may not all benefit equally from any single approach, necessitating the importance of targeted education and intervention. Thus, future initiatives for the prevention of cervical cancer must aim to decrease existing inequalities, with a strong emphasis on educating about HPV transmission and screening throughout a woman’s lifetime, particularly in groups where incidence and death rates are disproportionate. The hope is that these preventive methods – and in particular, the vaccine – will significantly reduce the HPV disease burden for future generations.
While progress in prevention must continue, complementary approaches that can provide better treatment options to populations that cannot directly benefit from vaccine-associated therapies must also be developed. These groups include women who are already infected with HPV, immunocompromised individuals such as those with HPV/HIV co-infections, and organ transplant patients. In treating these individuals, the prognosis and treatment of cervical cancer depends on our ability to medically diagnose and assign a disease stage. Therefore, improvements in diagnostic imaging, surgery, radiation therapy, chemotherapy, or a combination thereof are being studied to give women more options and to enhance each patient’s ability to make better-informed decisions.
Along with clinical treatment, molecular therapies that target cervical cancer processes are also anticipated to contribute to the elimination of cervical cancer. Research focusing on HPV early proteins will continue to provide insights regarding the viral mechanisms used to take control over cellular processes. Of these viral components, the E6 and E7 oncoproteins have long been recognized as the main mediators of HPV-associated malignancies. Therefore, the idea that approaches targeting these two oncoproteins are likely to act in an anti-oncogenic manner is quite reasonable. Such discoveries have the potential to exert a broad impact in the field of virology, as they will enable researchers to more fully understand virus-host interactions and how to better equip the body to respond to or even prevent infection.
In conclusion, cervical cancer research has come a long way, but there is still much more to be done to ensure that our accomplishments are not overshadowed by failures to educate, vaccinate, improve clinical management, and strengthen our knowledge about HPV. Indeed, it is quite possible that the challenge of HPV-mediated cervical cancer can be overcome in this generation, given the abundance of advancements, ideas and potential avenues that have been discussed here.
AcknowledgmentsThis work was partially supported by a grant from the National Institutes of Health 5R25GM060507, which provided support to WE.
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