January 2019 Issue

Cancer: Reducing Risk With Carotenoids
By Karen Collins, MS, RDN, CDN, FAND
Today's Dietitian
Vol. 21, No. 1, P. 12

Help clients increase their consumption and absorption of these powerful compounds.

For decades, carotenoids have been discussed as part of dietary choices for reducing cancer risk. However, understanding of carotenoids' role has become more complex since evidence has expanded to include stronger types of studies and as controlled trials with supplements haven't turned out as expected. This updated summary of research on dietary carotenoids and cancer risk can help dietitians develop accurate, evidence-based message points for talking to patients about healthful eating patterns.

Broad Family of Phytochemicals
Nature produces hundreds of the yellow, orange, and red pigments classified as carotenoids. Among the many in food, six are the most prevalent in human diets and account for the vast majority of circulating carotenoids.1 Alpha-carotene, beta-carotene, and beta-cryptoxanthin are the provitamin A carotenoids that can be converted within the body to retinol.2 Lutein, zeaxanthin (lutein's stereoisomer), and lycopene can't provide protection through vitamin A functions, but serve other health-protective roles.

Carotenoids and Cancer in the Big Picture
"Diet, Nutrition, Physical Activity and Cancer: a Global Perspective — The Third Expert Report," from the American Institute for Cancer Research (AICR) in association with the World Cancer Research Fund (WCRF), is today's most authoritative analysis of links between diet, physical activity, and cancer.3 The report doesn't identify a strong association of carotenoids with reduced risk of any cancer. It does, however, rate evidence "limited suggestive" for associations of foods containing beta-carotene with lower risk of lung cancer, and foods containing carotenoids with lower risk of lung and breast cancers. This classification of evidence indicates potential but isn't strong enough to support specific recommendations. Evidence is classified as "strong" that a substantial effect of beta-carotene on risk of prostate cancer is unlikely.

Breast cancer: Higher circulating levels of beta-carotene, lutein, and total carotenoids show clearest links to lower risk of breast cancer.3 The association is stronger for breast cancers that are estrogen receptor-negative (ER-) than estrogen receptor-positive (ER+). For ER- cancers, circulating alpha-carotene also shows a protective association.3,4 In laboratory studies, some carotenoids can inhibit growth of both ER+ and ER- breast cancer cells, so it's possible that their effect is simply overshadowed in human studies by the hormone-dependent effects that dominate in ER+ tumors.3 In an analysis within the Nurses' Health Study cohort, plasma carotenoids measured more than 10 years before diagnosis were related even more strongly with reduced risk than levels within 10 years, suggesting a potential role early in the disease process.1

Lung cancer: Dietary intake and serum levels of beta-carotene and total carotenoids are associated with lower risk of lung cancer in meta-analyses for the AICR/WCRF report.3 Studies were adjusted for current and past smoking intensity and duration. However, tobacco smoking reduces serum levels of beta-carotene, so the association of lower beta-carotene levels with greater risk may include some residual confounding of the influence of tobacco.3 In contrast, evidence is rated convincing that high-dose beta-carotene supplements increase lung cancer risk in current and former smokers.3

Prostate cancer: The AICR/WCRF paper reported no significant association of dietary, supplemental, or circulating levels of beta-carotene with prostate cancer risk.3 Lycopene has been connected with reduced risk, but research isn't definitive.5 Analyses in the AICR/WCRF report using only the highest-quality studies found no association of dietary or serum lycopene with risk of total, advanced, or nonadvanced forms of the disease. Another analysis encompassing additional studies, however, did link circulating lycopene with lower risk of advanced stage and aggressive prostate cancer, and with prostate cancers diagnosed before 1990, when prostate-specific antigen testing became widespread.5

More Than One Potential Way to Protect
Experimental studies have identified several different mechanisms through which carotenoids may act to reduce cancer development, including retinol, antioxidant actions, and cell signaling and communication functions.

Retinol supports the immune system and helps regulate cell growth and differentiation, according to cell culture and animal model studies. So this could account for part of the cancer protection from the three provitamin A carotenoids. However, evidence from human studies is too limited to draw any conclusion about the effects of vitamin A on cancer risk.3 The relationship between serum vitamin A levels or vitamin A supplementation and cancer risk is unclear, and clinical trials with vitamin A supplements haven't resulted in reduced cancer occurrence.6

Antioxidant defense support could be a significant factor in carotenoids reducing cancer risk. Reactive oxygen species (ROS), sometimes called free radicals, are produced as part of normal metabolic processes and are obtained through environmental exposure. Excessive levels of cellular ROS can cause DNA damage that initiates cancer development and promote chronic inflammation that's a hallmark characteristic enabling cancer development.2,3 Antioxidants either inactivate ROS or prevent chemical reactions they initiate.

Beta-carotene and lycopene are the carotenoids most clearly documented with antioxidant function in laboratory studies. Recent studies suggest beta-cryptoxanthin also may have this capacity.7 Even without direct antioxidant actions, carotenoids or metabolites formed from them may enhance endogenous antioxidant defenses, referred to as the antioxidant response element. In cell studies, carotenoids lead to upregulation of genes coding for a variety of antioxidant enzymes, such as glutathione S-transferases.2,8,9 However, evidence is currently limited regarding the extent of this protection in animal and human studies.

Cell signaling and communication with neighboring cells helps maintain cells in a differentiated state, inhibits cell proliferation, and induces both carcinogen-metabolizing enzymes and apoptosis (programmed destruction of abnormal cells). Laboratory studies suggest that carotenoids' effects on gene expression support these essential functions.3,8,10

Behind the Headlines
Although laboratory research identifies cancer-protective potential for carotenoids through these mechanisms, human studies in recent years have become more tentative in supporting links to lower cancer risk. This reflects multiple challenges in conducting and interpreting this research.

Type of study. Earlier human studies often involved a case-control methodology. This retrospective design is more prone to recall and other biases than prospective cohort and randomized controlled trials.3 For example, in meta-analyses of dietary and circulating lycopene on prostate cancer risk, significant protective associations were found in case-control studies and combined analysis of case-control and cohort studies, but not in the methodologically stronger prospective cohort studies.11

Consumed vs absorbed carotenoids. Nutrient data tables and apps list average carotenoid content. In addition to the natural variation in content, amounts actually absorbed may vary substantially depending on food preparation.12 Heat and mechanical processing weaken cell walls where carotenoids are stored in plants and enhance bioavailability. For example, an AICR/WCRF meta-analysis found no association between tomatoes (the major source of lycopene in the US diet) and overall or advanced prostate cancer risk.3 In addition, a recent analysis of studies on raw tomatoes didn't have a statistically significant link with risk of prostate cancer, although more frequent consumption of cooked tomatoes and sauces (in which lycopene is more bioavailable) was associated with reduced risk.13

Dietary context. Carotenoids are lipophilic compounds, and fat consumed at the same time enhances intestinal incorporation into micelles for absorption. Food preparation and other foods consumed at the same meal providing 3 to 8 g fat is sufficient to enhance absorption, which may be particularly valuable for raw vegetables.14,15 Moreover, although isolated carotenoids show potential for cancer risk reduction, animal studies show greater efficacy in a whole food than in isolated compounds, and in a combination of plant foods, such as tomatoes with broccoli or soy, than with tomatoes alone.16-18

Dietary vs circulating carotenoids. Plasma or serum carotenoid levels are considered better indicators of body exposure to these compounds than estimates of dietary intake.3,19 Using circulating carotenoids bypasses the challenges of assessing dietary intake and carotenoid bioavailability as well as individual differences in absorption and metabolism of carotenoids.19 However, circulating levels of carotenoids are established biomarkers of overall vegetable and fruit consumption.20 So an association of carotenoids with lower cancer risk could reflect effects of the multiple nutrients and phytochemicals obtained from increased produce intake.21

Solid Message Points
Current evidence on the diet's role in reducing cancer risk provides much stronger support for an overall plant-focused eating pattern than for emphasis on individual nutrients or phytochemicals. Points of emphasis include the following:

• Include nonstarchy vegetables and/or fruits at every meal.
• Expand variety among these choices for a wide range of nutrients and natural plant compounds that may each offer unique cancer-protective effects. As part of that variety, include choices that are dark green, deep orange, and red several times each week.
• Enjoy vegetables both raw and cooked. Moderate heating doesn't destroy carotenoids and makes it easier for the body to absorb more. However, don't cook vegetables in large pots of water or overcook them, since this could cause loss of other nutrients that are water soluble and heat sensitive.
• Don't fear fat. Oil in salad dressing or stir-fries, or modest amounts of fat in other foods at the same meal, makes it easier to absorb carotenoid compounds from food.
• Rely on food, not supplements, for carotenoids. Foods provide many different carotenoids, rather than only the beta-carotene or lycopene typically found in supplements. And extreme amounts aren't needed. Carotenoid levels associated with lower cancer risk come from realistic amounts of a variety of colorful fruits and vegetables.

— Karen Collins, MS, RDN, CDN, FAND, is a nutrition consultant specializing in cancer prevention and cardiometabolic health and nutrition advisor to the American Institute for Cancer Research.

References
1. Eliassen AH, Liao X, Rosner B, Tamimi RM, Tworoger SS, Hankinson SE. Plasma carotenoids and risk of breast cancer over 20 y of follow-up. Am J Clin Nutr. 2015;101(6):1197-1205.

2. Priyadarshani AM. A review on factors influencing bioaccessibility and bioefficacy of carotenoids. Crit Rev Food Sci Nutr. 2017;57(8):1710-1717.

3. Diet, nutrition, physical activity and cancer: a global perspective — the third expert report. World Cancer Research Fund website. https://www.wcrf.org/dietandcancer

4. Bakker MF, Peeters PH, Klaasen VM, et al. Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr. 2016;103(2):454-464.

5. Key TJ, Appleby PN, Travis RC, et al. Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies. Am J Clin Nutr. 2015;102(5):1142-1157.

6. Vitamin A: fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements website. https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/. Updated October 5, 2018. Accessed November 13, 2018.

7. Burri BJ, La Frano MR, Zhu C. Absorption, metabolism, and functions of β-cryptoxanthin. Nutr Rev. 2016;74(2):69-82.

8. Li W, Guo Y, Zhang C, et al. Dietary phytochemicals and cancer chemoprevention: a perspective on oxidative stress, inflammation, and epigenetics. Chem Res Toxicol. 2016;29(12):2071-2095.

9. Kaulmann A, Bohn T. Carotenoids, inflammation, and oxidative stress — implications of cellular signaling pathways and relation to chronic disease prevention. Nutr Res. 2014;34(11):907-929.

10. Khuda-Bukhsh AR, Das S, Saha SK. Molecular approaches toward targeted cancer prevention with some food plants and their products: inflammatory and other signal pathways. Nutr Cancer. 2014;66(2):194-205.

11. Rowles JL 3rd, Ranard KM, Smith JW, An R, Erdman JW Jr. Increased dietary and circulating lycopene are associated with reduced prostate cancer risk: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2017;20(4):361-377.

12. Bohn T, McDougall GJ, Alegría A, et al. Mind the gap — deficits in our knowledge of aspects impacting the bioavailability of phytochemicals and their metabolites — a position paper focusing on carotenoids and polyphenols. Mol Nutr Food Res. 2015;59(7):1307-1323.

13. Rowles JL 3rd, Ranard KM, Applegate CC, Jeon S, An R, Erdman JW Jr. Processed and raw tomato consumption and risk of prostate cancer: a systematic review and dose–response meta-analysis. Prostate Cancer Prostatic Dis. 2018;21(3):319-336.

14. Moran NE, Johnson EJ. Closer to clarity on the effect of lipid consumption on fat-soluble vitamin and carotenoid absorption: do we need to close in further? Am J Clin Nutr. 2017;106(4):969-970.

15. van Het Hof KH, West CE, Weststrate JA, Hautvast JG. Dietary factors that affect the bioavailability of carotenoids. J Nutr. 2000;130(3):503-506.

16. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, Clinton SK. Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Nat Cancer Inst. 2003;95(21):1578-1586.

17. Canene-Adams K, Lindshield BL, Wang S, Jeffery EH, Clinton SK, Erdman JW Jr. Combinations of tomato and broccoli enhance antitumor activity in dunning r3327-h prostate adenocarcinomas. Cancer Res. 2007;67(2):836-843.

18. Zuniga KE, Clinton SK, Erdman JW Jr. The interactions of dietary tomato powder and soy germ on prostate carcinogenesis in the TRAMP model. Cancer Prev Res (Phila). 2013;6(6):548-557.

19. Aune D, Chan DS, Vieira AR, et al. Dietary compared with blood concentrations of carotenoids and breast cancer risk: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr. 2012;96(2):356-373.

20. Pennant M, Steur M, Moore C, Butterworth A, Johnson L. Comparative validity of vitamin C and carotenoids as indicators of fruit and vegetable intake: a systematic review and meta-analysis of randomised controlled trials. British J Nutr. 2015;114(9):1331-1340.

21. Farvid MS, Chen WY, Rosner BA, Tamimi RM, Willett WC, Eliassen AH. Fruit and vegetable consumption and breast cancer incidence: repeated measures over 30 years of follow-up [published online July 6, 2018]. Int J Cancer. doi: 10.1002/ijc.31653.

ADVERTORIAL