Prostate Cancer Prevention Vitamin A Biology Essay

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The term vitamin A stands for two main groups of compounds; the pre-formed vitamin A (retinol, retinaldehyde, retinoic acid) and the vitamin A precursors, which include the hydrocarbons or carotenes (α-carotene, β-carotene, lycopene) and oxygen-containing carotenoids or xanthophylls (cantaxanthin, zeaxanthin, astaxanthin, lutein). All forms of vitamin A are fat-soluble molecules that are absorbed with lipids in the small intestine forming micelles and are transported to the liver using chylomicrons. Almost 80% of dietary pre-formed vitamin A is absorbed, whereas the absorption of carotenes depends on the nature and procession of the food and can be up to 60%. Some carotenes can be converted into retinol, a chemical reaction catalyzed by carotene dioxygenase (Bender 2008). Natural sources of all vitamin A forms are shown in Table 1. Retinol and its compounds are mainly found in foods of animal origin, such as liver, oily fish and milk. On the contrary, red and orange-coloured fruit and vegetables as well as green leafy vegetables are main sources of carotenoids. (Krinsky et al. 2005).

Vitamin A is involved in vision and in protein synthesis from the DNA, which leads to cellular and tissular differentiation and, therefore, growth, development and reproduction. Carotenes may show an additional action as antioxidants, especially in tissues where there is low concentration of oxygen (Bender 2008). The continuous study of vitamin A focuses on its role on various cellular processes. A lot of research has been conducted to show potential effects of vitamin A on cardiovascular diseases and different forms of cancer.

Prostate and prostate cancer

Prostate is an organelle next to the urethra and it weighs 20 - 30 grams in an adult man. It acts as a gland, releasing ions, enzymes and organic molecules such as spermine to prevent pathogens from entering the reproductive system of men. The prostate epithelium consists of three types of cells, each of which has a specific role. The secretory cells produce the prostate - specific androgen (PSA) and express the androgen receptor (AR), the basal cells produce secretory cells when needed, and the neuroendocrine cells excrete a range of different molecules (Steers 2011).

Table 1: Food products rich in different forms of vitamin A (Krinsky et al. 2005).

Forms of vitamin A

Food products

Retinol and compounds

liver

oily fish

milk and dairy products

butter

fortified margarine

β-carotene

carrots (raw and cooked)

mango

sweet potato (cooked)

spinach

cabbage

winter squash (pumpkin)

lettuce

tomato

broccoli

apricot

cantaloupe

melon

orange

Lycopene

tomato (raw, cooked, canned, paste, puree, sauce, juice, soup)

Watermelon

red (bell) peppers

pink or red grapefruit

pink-fleshed guava

persimmons

Lutein, zeaxanthin

spinach

cabbage

lettuce

broccoli

Prostate cancer is an adenocarcinoma (main type of cancer for glandular tissues), representing 12% of all cancers among men worldwide and 19% of all cancers in developing countries. It is the second most common cancer among men, in a rate of 25.3 incidences per 100,000 people, and 76% of them occurred in men living in developed countries (Baade et al. 2009). The main risk factor for prostate cancer is age, as incidence rises sharply after 40 years of age (Table 2). Other established risk factors include race and geography, whereas environmental factors such as smoking, obesity, alcohol and dietary fat intake have been proposed but not yet proven. The role of nutrition in prostate cancer development remains controversial and research focuses on antioxidant compounds, such as vitamin A (Willis et al. 2003). The main hypothesis is that vitamin A may has a protective role against prostate cancer, as it inhibits cell proliferation and induces cell apoptosis in many organs and tissues such as the prostate (World Cancer Research Fund / American Institute for Cancer Research 2007).

Table 2: Incidence rate of prostate cancer according to age (Baade, Youlden et al. 2009).

Age (years)

Incidence rate (per 100,000 population)

15-44

0.2

45-54

10.6

55-64

72.9

>65

259.6

Retinol (retinoids) and prostate cancer

Retinol is a compound of retinoids and one of the functional forms of vitamin A in the human body (Bender 2008). A few studies have been conducted to examine possible associations of serum or plasma retinol and the risk of developing prostate cancer, both localised and aggressive. Main values of estimating retinol status were serum retinol, which is proven to be the most accurate measure of retinol status, and retinol dietary intake. Results from retinol studies are controversial and most of them show no association of high serum retinol and prostate cancer. The most recent published study concerning plasma retinol and prostate cancer was a large nested case - control study from the Prostate Testing for Cancer and Treatment (ProtecT) trial. No association or trend of plasma retinol levels and overall [Odds Ratio OR: 0.95, 95% Confidence Interval (0.74, 1.22), p for trend = 0.19] or aggressive prostate cancer risk was found (Gilbert et al. 2012). These results are also supported by other studies (Key et al. 2007, Goodman et al. 2003, Huang et al. 2003, Beilby et al. 2010, Gill et al. 2009, Karppi et al. 2012), where no statistically significant associations were found in either localised or aggressive prostate cancers.

However, some studies show significant, but mixed results. A large cohort study associated high retinol levels with 20% higher risk of developing any stage of prostate cancer in the follow-up period (5th quintile of retinol levels against 1st quintile OR: 1.18, 95%CI 1.01, 1.38, p for trend = 0.02). After follow-up, men at the 5th quintile both at baseline and the follow-up had the greatest risk of prostate cancer (Mondul et al. 2011). This study included only smokers, suggesting a possible smoking - retinol inverse association. On the other hand, two studies (Beydoun et al. 2011, Schenk et al. 2009) presented an inverse correlation between high plasma retinol and the risk of prostate cancer and one of them pointed out a significant reduction in aggressive prostate cancer (Schenk et al. 2009).

Apart from serum retinol, serum retinyl palmitate esters were measured in a study (Huang et al. 2003, Beilby et al. 2010) which showed inverse associations with prostate cancer risk, suggesting retinol's antiproliferative value. What is more, one study used retinol and β-carotene - which converts to retinol in some extent in human body - supplements to increase retinol intake and showed increased prostate cancer risk on extreme high serum retinol (Neuhouser et al. 2009). Consequently, it is difficult to estimate whether retinol or retinol compounds have a significant effect on prostate cancer risk. Furthermore, most of the studies had certain limits such as small sample (Beilby et al. 2010, Karppi et al. 2012) and inability to rule out confounding factors (Karppi et al. 2012, Neuhouser et al. 2009).

Β-carotene and prostate cancer

B-carotene is the main form of vitamin A deriving from the plants and a compound with potent antioxidative value. However, results from studies are conflicting and no estimation can be made on prostate cancer risk. Most studies show no association between serum β-carotene levels and the risk of developing prostate cancer (Key et al. 2007, Goodman et al. 2003, Huang et al. 2003, Gill et al. 2009, Beydoun et al. 2011, Lu et al. 2001) and few present either a negative (Karppi et al. 2012, Neuhouser et al. 2009, Vogt et al. 2002, Zhang et al. 2007) or a protective effect (Wu et al. 2004, Chang et al. 2005, Bosetti et al. 2004).

Key et al. (2007) examined the association of plasma carotenoids and prostate cancer risk in the European Prospective Investigation into Cancer and nutrition (EPIC) study, and found no significant associations in either localized or aggressive stage. However, the higher the serum levels of total carotenoids, the lower the incidence of aggressive prostate risk (highest quintile against lowest quintile: OR: 0.35, 95% CI 0.21, 0.98, p for trend = 0,04), suggesting a probable synergistic action of all carotenoids in the prostate tissue. On the other hand, Neuhouser et al. (2009) had opposite results, using a supplement of β-carotene and retinyl palmitate. However, there can be no estimation whether β-carotene, retinyl palmitate, or further supplementation were responsible for this result. Moreover, two studies separated their case and control samples according to their race and one of them found significant increase in prostate cancer risk among Blacks (OR: 2.43, 95% CI not presented, p<0.05) (Vogt et al. 2002), while the other did not (Zhang et al. 2007). However, low participation was the major limitation of both studies.

The evaluation of dietary β-carotene, apart from serum β-carotene only, may have more significant results. A large study which evaluated serum and dietary carotenoids showed an inverse correlation of serum β-carotene and prostate cancer risk in all participants, but statistically significant only in men under 65 years old (highest quintile against lowest quintile OR: 0.36, 95% CI 0.14, 0.91, p for trend = 0.03). Also, when total β-carotene was evaluated (blood and dietary), men in the highest quintile of plasma/dietary scores had a 77% reduced risk of developing prostate cancer, compared to the lowest quintile, but the sample was too small to assess a statistical significance (p for trend = 0,15) (Wu et al. 2004).

Lycopene and prostate cancer

Lycopene is a carotenoid compound that does not convert to vitamin A, therefore it does not have any vitamin A activity. Nevertheless, several studies have been conducted on lycopene intake and different forms of cancer, due to its antioxidant properties. Interest is increased, as lycopene is present on prostate tissue and is shown to have specific effects on prostate cancer development (Krinsky et al. 2005). There has been more thorough research on lycopene rather than retinol and β-carotene according to prostate cancer and different study designs have been used.

Two clinical trials used 30 mg lycopene supplementation in the intervention group and observed differences from a control group. Only one study presented significantly lower prostate - specific antigen results (biomarker of prostate cancer) because of lycopene supplementation (Schwarz, et al. 2008) whereas the other two showed no effects on PSA levels before and after the trial (Van Breemen et al. 2011, Bunker et al. 2007), although serum lycopene levels were significantly higher in all intervention groups. The trials were either too small or too short to evaluate the long term effects of lycopene supplementation. Serum lycopene levels were also the marker of lycopene status in nine case - control studies. Five cohort and one retrospective studies did not relate lycopene to overall prostate cancer risk or showed non-significant trends whereas one cohort and three retrospective studies showed a strong inverse relation of high lycopene consumption and prostate cancer risk, especially for advanced stages (Tables 3 and 4).

Table 3: Prospective studies of plasma/serum lycopene and overall prostate cancer risk*: Odds Ratios (OR) and 95% Confidence Intervals (95% CI) for the highest compared with the lowest lycopene concentration in each study.

Study

Year

Sample (cases/controls)

OR (95% CI)

Peters et al.

2007

692/844

1.14 (0.82-1.58)

0.99 (0.62-1.57) aggressive

Kristal et al.

2011

1809/1809

0.99 (0.94-1.04) Gleason score 2-6

1.01 (0.94-1.08) Gleason score 7-10

Huang et al.

2002

184/364 (CLUE I)

142/284 (CLUE II)

0.83 (0.46-1.48)

0.79 (0.41-1.54)

Beilby et al.

2010

96/226

0.77 (0.40-1.47)

Wu et al.

2004

450/450

0.66 (0.38-1.13)

Key et al.

2007

966/1064

0.97 (0.70-1.34)

0.40 (0.19-0.88)** aggressive

* Aggressive prostate cancer risk or Gleason score is also referred in some studies

** p<0.05

Dietary lycopene is consumed mainly through tomatoes and tomato products. Several studies investigated the relation of tomato and tomato products consumption and prostate cancer risk. Three case control studies from Iran, Auckland and Italy showed no significant association between high tomato consumption and prostate cancer risk

Table 4: Retrospective studies of plasma/serum lycopene and overall prostate cancer risk*: Odds Ratios (OR) and 95% Confidence Intervals (95% CI) for the highest compared with the lowest lycopene concentration in each study.

Study

Year

Sample (cases/controls)

OR (95% CI)

Chang et al.

2009

118/52

1.30 (0.63-2.71)

Zhang et al.

2007

193/197

0.46** (0.22-0.94)

Vogt et al.

2002

209/228

0.65 (not presented, p for trend = 0.09)

0.37** (not presented, p for trend = 0.04) aggressive

Lu et al.

2001

65/132

0.17** (0.04-0.78)

* Aggressive prostate cancer risk is also referred in a study

** p<0.05

(Bosetti et al. 2004, Pourmand et al. 2007, Norrish et al. 2000), but they contained small samples and evaluated lycopene consumption from a single Food Frequency Questionnaire (FFQ). On the other hand, Giovannucci et al. (2002) conducted a prospective dietary study that used multiple dietary assessments to estimate lycopene intake and found a protective effect of high lycopene consumption (OR: 0.84, 95% CI 0.73, 0.96, p for trend = 0.003) and especially tomato sauce consumption (OR: 0.77, 95% CI 0.66, 0.90, p for trend < 0.001) on prostate cancer risk, mostly in older men. On the contrary, two prospective dietary studies showed null results (Kristal et al. 2010, Kirsh, et al. 2006). Factors that may contribute to inconsistent results in lycopene studies include low tomato consumption in some populations, incomplete Food Frequency Questionnaires and low effectiveness of a single dietary assessment, as prostate cancer progression is very low.

Other carotenoids and prostate

Other carotenoids include α-carotene, γ-carotene and β-cryptoxanthin, which convert in vitamin A as well as lutein and zeaxanthin that, as lycopene, do not have vitamin A activity. Studies examine several types of carotenoids and total prostate cancer risk, but results lack significance. Lutein and zeaxanthin are usually measured as one carotenoid and only two studies found a statistically significant protective role against prostate cancer (Lu et al. 2001, Chang et al. 2005). However, samples in these studies were very small and examined specific populations. On the other hand, other studies did not relate any carotenoid with prostate cancer (Gill et al. 2009, Beydoun et al. 2011). Moreover, results on high serum α-carotene levels suggest either a decrease (Beydoun et al. 2011) or an increase (Karppi et al. 2012) in total prostate cancer risk, but most of them show null association (Huang et al. 2003, Vogt et al. 2002). Only one study showed a possible benefit of high serum β-cryptoxanthin levels (Lu et al. 2001). Finally, γ-carotene is estimated only in Goodman et al. study (2003) and no significant results were found. Overall, there seems to be no effect of other carotenoids in the development of prostate cancer, although lack of associations may be due to poor study designs.

POTENTIAL MECHANISMS

All forms of vitamin A are proposed to have properties that protect the tissues from uncontrollable cell proliferation that leads to tumors. The main form of vitamin A that circulates in the human body is retinol, because β-carotene and several other carotenoids convert to this vitamin A form. Although retinol is known to have anticarcinogenic action, high intraprostatic levels of retinol are shown to increase cell proliferation. Nevertheless, it is not known whether high serum retinol levels are related to high intraprostatic levels. Generally, retinol has the ability of inducing cell apoptosis and regulating cell proliferation. A possible mechanism is retinol's action on the transcription of by inhibiting the activity of DNA polymerase in the G1 phase of the cell cycle. What is more, vitamin A has no antioxidant effects; instead it promotes the action of other vitamins, such as vitamin E and minerals, such as selenium, known for their ability to donate an electron and to destroy free radicals (Willis 2003).

Lycopene is one of the few carotenoids that cannot convert to retinol, suggesting a different role from vitamin A. It is one of the most active antioxidants, regulating cell proliferation, low-density lipoprotein cholesterol, immune system and inflammation. The role of lycopene in prostate cancer is found on the regulation of serum insulin-like growth factor-1 (IGF-1), which is one of the potential factors that promote prostate cancer (Willis 2003).

CONCLUSION

Great interest has arisen in the association of nutrition factors and the risk of different types of cancer. Prostate cancer is the second most common cancer and represents about 7% of all cancer-related deaths among males worldwide (2002). Potential benefits from the consumption of antioxidants such as different forms of vitamin A have examined. All compounds except for lycopene have yet failed to prove their antioxidant effects on prostate cancer risk. Most studies have presented inconsistent or ono-significant results. Uncertainty of potential benefits of several carotenoids and retinol consumption leads to further research on the field of prostate cancer prevention.

On the other hand, several studies have shown that high lycopene consumption mainly from food products may reduce prostate cancer risk, although in some of them the results are not significant. A recent review from Wei et al. (2012) failed to show a reduction in total prostate cancer risk due to high lycopene intake. In the review, it is stated that earlier studies have presented promising results but it was due to a limited interest on lycopene research. As interest grew, recent studies were better organised and did not support previous findings. Moreover, studies published before Prostate - Specific Antigen screening was established may have linked the positive effects of lycopene intake particularly with aggressive types of prostate cancer, whereas most recent studies show inconsistent results on non-aggressive types of prostate cancer.

Vitamin A is an essential vitamin for vision, gene expression and cell differentiation. Consequently, it acts on a variety of tissues apart from the prostate tissue. Prostate cancer is one of the most common types of cancer and it is a great issue of public health, leading to lower quality of life and increased funds on medical care and medicines. Further research on the fields of vitamin A compounds and prostate cancer risk is required, so as to reveal potential protective action of antioxidants in the prostate tissue and be used as components in preventive medicine or factors that alter the development of prostate cancer into aggressive stages.

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