Chih HJ, Lee AH, Colville L, et al. Nutrition and Cancer. Volume 65, Issue 3, 2013. Pp. 317-328. DOI: 10.1080/01635581.2013.757630.
The natural history of cervical cancer suggests that prevention can be achieved by modification of the host’s immune system through a nutrient-mediated program. This study reviews the preventive role of dietary intake on cervical intraepithelial neoplasia (CIN) induced by human papillomavirus (HPV). Electronic databases were searched using relevant keywords such as, but not limited to, human papillomavirus infection, cervical intraepithelial neoplasia, lifestyle factors, nutrients intake, and diet. High consumption of fruit and vegetables appears to be protective against CIN. The findings also highlight the possibility of consuming high levels of specific nutrients, vitamins, and minerals, and retaining sufficient level of these elements in the body, especially those with high antioxidants and antiviral properties, to prevent progression of transient and persistent HPV infections to high-grade CIN 2 and 3 (including in situ cervical cancer). The protective effect is not significant for high-risk HPV persistent infections and invasive cervical cancer. Although it appears that intake of specific nutrients, vitamins, and minerals may be good in CIN prevention, there is lack of evidence from controlled trial to confirm this. Health professionals shall focus on implementation of a balanced-diet prevention strategy at an early stage for cervical cancer prevention.
With a prevalence of 10%, cervical cancer is the second most common cancer (after breast cancer) affecting women around the world (1). Although vaccination and safe sex education are effective in preventing the development of cervical intraepithelial neoplasia (CIN) to cervical cancer (2), women from many developing countries are not provided with such services. The morbidity rates of cervical cancer are therefore higher in these countries (3,4). It is predicted by 2020, if the risks and population growth remain constant as year 2002, there will be a 42% increase in cervical cancer cases (a total of 702,500 cases) if no novel preventive interventions are undertaken (3). The high incidence and cost to screen, treat, and provide psychological support contribute to the large economic burden of the disease (5).
It is well established that deficiencies of dietary vitamins, minerals, and nutrients can lead to DNA damage and immune-incompetence, permanent genetic alteration, and subsequently, a higher risk of cancer (6–11). New nutrient-mediated prevention strategies are implemented to stimulate host’s cell-mediated immune response against the viral oncogenes E6 and E7 (2,7). The constant expression and transforming properties of E6 and E7 genes and their interaction with the host cell proteins are indeed essential for the development of cervical cancer (12). The natural history of human papillomarvirus (HPV) infected high-grade cervical intraepithelial neoplasia (CIN) to cervical cancer suggests that prevention can be stimulated via the immune system (12–15). The underlying principle of the nutrient-mediated prevention strategy is the ability of a particular dietary constituent to interact with metabolising enzymes and proteins and regulate DNA methylation, synthesis, and chromatin organization that prevent DNA damage (9,16,17).
Consuming foods, particularly plant-based foods, that support normal DNA methylation has the potential to suppress expression of viral oncogenes, promote proper signalling pathways, avoid cell transformation, and reduce the risk of cancer in human (2,6,9). It has been documented that cruciferous vegetables have the ability to induce apoptosis through bioactive isothiocyanates and indoles (18–20). Vitamins such as vitamin A (retinoic acid), C (ascorbic acid), and E (tocopherol) can inhibit proliferation of cancer cells (17,21), stabilize the p53 protein (9), prevent DNA damage and reduce immune-suppression (11,17,22), and support the receptor signal transduction pathways (22). The membrane-modifying effects of long-chain fatty acids have also demonstrated positive effect in cancer prevention as docosahexaenoic acid induce mitochrondria-mediated apoptosis (23) and alter the receptor signal transduction pathway to activate lymphocyte proliferation (11). In addition, the active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 was found to have the ability to avoid cell proliferation (10,24). The antiviral property of minerals such as selenium and iron, while reliant on the activity of macrophages to produce nitrogen oxide, are also beneficial for cancer prevention (11).
FIG. 1 Selection process of publications included in this review following the preferred reporting items for systematic review and meta-analyses approach.
Following HPV infection, it takes six years on average before progressing to high-grade CIN including cervical cancer (5). Although the literature has suggested the role of diet in gene expression and cancer prevention, the relationship between a specific dietary constituent and the amount required to prevent cancer are not well established. Most of the studies were also based on animal models or in vitro. With the high disease burden of CIN, it is necessary to improve the understanding of dietary intake in the prevention of CINs and cervical cancer. The present review will examine recent evidence from epidemiological studies and randomized clinical trials with the aim to elucidate a better understanding about the role of diet in CINs prevention at an early stage.
Material and Methods
A search was conducted on the MEDLINE and Web of Knowledge databases in February 2012 to identify relevant articles. For the purpose of this review, the nomenclature used by the Australian Modified Bethesda System 2004 is followed; low-grade CIN includes HPV infection (both transient and persistent infections), high-grade CIN includes CIN 2 and 3, whereas cervical cancer includes in situ carcinoma and invasive cervical cancer (25).
Keywords used for searching the electronic databases were human papillomavirus infection OR cervical cancer OR carcinoma in situ OR cervical intraepithelial neoplasia OR cervix neoplasia OR cervix neoplasm AND lifestyle factors OR diet OR foods and nutrients intake OR nutrition OR dietary intakes OR food groups OR vitamins OR minerals OR antioxidants OR anticancer OR immunological prevention AND cohort study OR case-control study OR cross-sectional study OR trial. Only peer-reviewed, full-text articles written in English and published after the year 2000 were selected. The topic and abstract were initially screened to determine their eligibility for inclusion. Reference lists of the eligible articles were also manually searched for additional papers. The selection process adopted the preferred reporting items for systematic review and meta-analyses (PRISMA) approach (26).
Following the PRISMA approach, a total of 22 articles are selected (Fig. 1). There are 3 cross-sectional studies, 7 cohort studies, 11 case-control studies, and 1 randomized controlled trial. The majority (95%) are observational studies, with about 48% conducted in the United States, followed by 33% in Asian countries and the rest from Europe and Brazil. All of the studies were conducted on women over the age of 18.
The results are organized and presented in terms of whole food intake (Table 1), nutrients, minerals and vitamins intake (Table 2), and circulating plasma or serum nutrients (Table 3), in relation to the risk of HPV infection, CIN 1, 2, and 3. In the reviewed publications, the adjusted odds ratio estimated the association between the exposure variable of interest and the development of HPV infection and CIN, while accounting for the effects of other plausible confounding factors.
As summarized in Table 1, the epidemiological evidence suggested that high intake of certain whole foods may be protective against HPV transient infections. The results highlighted the benefits of high consumption of whole fruits and vegetables, nuts, and fish. Meanwhile, low consumption of whole vegetables (including dark green-, dark yellow-, dark orange-colored vegetables, and cruciferous vegetables), fruits (including fruit juices), yogurt, tofu, fish and meat, are not protective against HPV persistent infection, CIN 1, 2, and 3. Low intakes of fruits and vegetables are associated with three-fold increase in the risk of CIN 2 and 3 in subjects with high HPV viral load (27). Therefore, high-risk patients, especially those infected by high risk HPV types, should increase and maintain their fruits and vegetables intake at moderate levels. This recommendation is supported by findings presented in Table 2. Consumption of foods that provide rich sources of retinol and vitamin A, bioavailable calcium, antioxidants (including vitamin C, E, carotene, lutein and lycopene), as well as long-chain polyunsaturated fatty acids, can significantly reduce the risk of in situ cervical cancer. We believe that the antioxidant and/or antiviral activities from these whole foods contribute to the observed risk reductions.
Table 3 illustrates the relationship between circulating bioactive compounds (and their isomers) and risk of HPV-related diseases. The findings are consistent with the reported protective effects of nutrients, vitamins, and minerals in Table 2. It appears that large amounts of whole foods should be consumed at an early stage to maximize their beneficial effect. For instance, circulating ascorbic acid (vitamin C) is not effective in preventing progression beyond HPV persistent infections. Similar results are observed between alpha tocopherol, gamma tocopherol, total carotene, and the risk of CIN.
Low serum levels of lycopene, retinol, alpha tocopherol, and gamma tocopherol tended to be positively associated with risk of CIN 3, whereas medium to high levels of serum alpha-carotene, beta-cryptoxanthin, lutein/zeaxanthin, gamma tocopherol, and particularly serum lycopene could reduce the risk of high-grade CIN (Table 3). It has been suggested that some antioxidants may be effective in preventing high-grade CIN if it was initiated from the stage of cervical inflammation that promoted HPV infections, rather than directly infected by HPV (28). Their molecular structures can interact with the receptors and substrates within the host’s cells and either regulate the activity of reactive oxygen species, which in turn inhibit transcription factor (activator protein1, AP1) and expression of oncogenes E6 and E7, reduce immunosuppression, stabilize p53 protein, or prevent DNA damage (9,11,22,28). As a result, these antioxidants have different abilities to intervene the natural history of HPV-infected diseases.
Vitamin A (retinoid acid) is essential for the replication of basal and mucous cells and synthesis of protein blocks (11). Vitamin A deficiency may thus lead to a higher risk of squamous metaplasia and infection. Therefore, a low-to-medium level of serum retinol is only effective in reducing the risk of low-grade CIN (Table 3). Retinoids have the ability to inhibit cell proliferation as their isoform retinoic acid receptors (RARβ2) stimulate the transcription of RARβ2 tumor suppressor, diminish formation of AP1 that regulates expression of oncogenes, and prevent cell proliferation and induce apoptosis while enhancing the expression of p53 proteins (19). Consequently, sufficient amount of retinoic acids in the blood can prevent progression of a low-grade CIN to high-grade CIN.
It is well known that folate plays an important role in DNA synthesis, repair, methylation and cell proliferation (29,30). Low folate levels are linked to weaker structure of DNA and thus more prone to DNA damage induced by virus and subsequent expression of the viral oncogene (17). As illustrated in Table 3, a low level of serum folate is associated with a higher risk of both low- and high-grade CIN, whereas medium levels of serum folate lead to a higher risk of low-grade CIN but not high-grade CIN. As folate can initiate DNA repair, methylation, and expression of viral oncogenes, increasing the level of serum folate may provide an effective intervention in high-grade CIN preventions.
Circulating antioxidants, at high levels, can enhance the clearance of high-risk HPV infections and transient high-risk HPV infections by up to three- and fourfold, respectively (Table 3). In this regard, lycopene has emerged as the most effective. In contrast, as HPV infections evolve from transient to persistent, there is no significant increment in clearance of persistent HPV infections with any levels of plasma circulating nutrients. This relationship stresses the importance of early intervention and prevention of HPV-related diseases. Nutrients, vitamins, and minerals are important in regulating viral integration and gene stability and preventing cancer development (17).
It appears that high consumption of whole foods has little benefit for the prevention of persistent HPV infections and beyond (Table 1), which is consistent with other studies (17,22,31). It should be noted that these studies investigated the effect of a particular food group but not the whole spectrum of food groups. The World Cancer Research Fund recommends the consumption of a wide variety of whole foods, as they naturally contain various nutrients, vitamins, minerals, and bioactive compounds not found in a specific type of supplement (32). The synergistic effect of all food groups was not examined in these studies, which could have masked the protective effect of whole food intake on HPV infections and CIN. Dietary supplements should only be taken by those with a specific nutritional deficiency rather than for the purpose of cancer prevention (32–34). In addition, the problem of collective error (33) should not be ignored. Moreover, explanation for the observed phenomenon cannot be elucidated without information on the history of the infection status of participants involved in the studies.
Despite the emerging evidence from these studies, several limitations should be taken into consideration. Only one prospective study had investigated the association between nutrients and cervical cancer. The majority of the observational studies are prone to biases. These include information bias with reliance on a standard serving of fruit and vegetables, recall bias of past dietary history, and the inability of the cross-sectional studies to establish a cause-and-effect relationship. In addition, the controls in these epidemiological studies should ideally be women exposed to HPV infection to enable a fair comparison of the risk of HPV-related diseases (35). The effect of polyphenols as antioxidants and enzyme inhibitors on the development of cervical cancer has also been overlooked (36). Well-designed controlled clinical trials are needed to confirm the observed associations between nutrients and cervical cancer. Until then, clinicians should encourage those at risk to take up healthy eating habits.
High consumption of certain nutrients, vitamins, and minerals, particularly those with antioxidant and antiviral properties, appears to be effective in preventing HPV infections from progressing to high-grade CINs. Further evidence from human clinical trials is required to confirm the relationship. Health professionals should continue to recommend consumption of a wide variety of whole foods rich in these nutrients, vitamins and minerals. Dietary supplements should only be taken when these micronutrients are deficit in the food system of the under-nourished populations.
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