beta-Carotene fails to act as a tumor promoter, induces RAR expression, and prevents carcinoma formation in a two-stage model of skin carcinogenesis in male Sencar mice

Our plain-English summary of beta-Carotene fails to act as a tumor promoter, induces RAR expression, and prevents carcinoma formation in a two-stage model of skin carcinogenesis in male Sencar mice, by R.M. Ponnamperuma, Y. Shimizu, S.M. Kirchhof, et al (Nutrition and Cancer, 2000).

The study

• Authors: R.M. Ponnamperuma, Y. Shimizu, S.M. Kirchhof, L.M. De Luca
• Journal: Nutrition and Cancer
• Published: 2000;37(1):82-8
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Clinical trials have shown a significant increase in incidence of lung cancer among smokers and asbestos workers supplemented with beta-carotene, suggesting a tumor-promoting activity for this agent. We set out to test possible tumor-promoting and chemopreventive activities of dietary and topical beta-carotene in the two-stage 7,12-dimethylbenz[a]anthracene-12-O-tetradecanoylphorbol 13-acetate (TPA) model of mouse skin carcinogenesis. In the first study, the effects of three levels of dietary beta-carotene (6, 60, and 600 micrograms/g purified diet containing no other retinoid or carotenoid) were assessed over a period of 42 weeks. Carcinoma yield was reduced by approximately 50% in the 600 micrograms/g diet group (mean 0.22 carcinomas/mouse) compared with the 6 micrograms/g diet group (mean 0.44 carcinomas/mouse, p = 0.003). The 60 micrograms/g diet group showed a pattern of inhibition similar to the 600 micrograms/g diet group. A protective effect (25% reduction) of beta-carotene (in the 600 micrograms/g diet group) on papilloma formation was also found. However, the intermediate 60 micrograms/g diet group showed the same incidence as the low 6 micrograms/g diet group. This points to a lack of correlation between papilloma and carcinoma incidence, as we also found in previous work on dietary retinoids and carotenoids. The purpose of the second study was to assess whether topical beta-carotene (2 micrograms) has tumor-promoting or chemopreventive activity in the two-stage protocol. In the absence of TPA, beta-carotene had no significant tumor-promoting activity. Instead, papilloma yield induced by TPA was decreased by topical beta-carotene from an average of 20 to approximately 10 papillomas/mouse (p = 2.5 x 10(-7)). The effect of topical beta-carotene persisted beyond the treatment period (Week 24) until the termination of the study at Week 42. Western blot analysis of mouse skin extracts showed that topical beta-carotene upregulated retinoic acid receptor-alpha and -gamma expression in the dorsal skin. This finding suggests that beta-carotene may work as a chemopreventive agent by upregulating the expression of retinoid receptors in mouse skin. In conclusion, our data show that beta-carotene prevents skin carcinoma formation, induces retinoic acid receptor expression, and fails to act as a tumor promoter in the two-stage model of skin tumorigenesis.

In plain English

This was a laboratory experiment in male Sencar mice, not a study of people or asbestos. The authors noted that earlier human trials, not part of this study, had linked beta-carotene supplements to more lung cancer in smokers and asbestos workers. They tested whether beta-carotene promotes or prevents mouse skin tumors. Tumors were started with one skin application of the chemical DMBA and, in most groups, promoted with weekly TPA. In a diet study of 156 mice fed 6, 60 or 600 micrograms of beta-carotene per gram of diet, carcinomas per mouse (counting mice alive when the first carcinomas appeared) averaged 0.22 in the 600 and 60 groups versus 0.44 in the 6 group. In a second study, beta-carotene applied to the skin did not significantly promote tumors without TPA. In TPA-treated mice, papilloma yield averaged 10 per mouse with beta-carotene versus 20 without. Treated skin showed more of two retinoic acid receptors. The authors concluded that beta-carotene fails to act as a tumor promoter in this model and prevents skin carcinoma. They said the mechanism remains to be established.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: two-stage (DMBA initiation, TPA promotion) mouse skin carcinogenesis model, with a dietary study and a topical study, plus Western blot analysis of retinoic acid receptors in skin
• Who was studied: Male Sencar mice. Dietary study: 156 mice (48, 53 and 55 in the 6, 60 and 600 µg/g diet groups). Topical study: four groups of 25, 25, 10 and 10 mice. Studies ended at 42 weeks of age.
• Exposure: Beta-carotene (all-trans, synthetic): in purified vitamin A-deficient diets at 6, 60 or 600 µg per gram of diet, or applied to the skin weekly at 2 µg in the solvent THF. Tumors were initiated with DMBA and promoted with TPA. No asbestos exposure was studied.
• Main results:
  • Dietary study: mean carcinoma yield (cumulative carcinomas divided by the number of mice alive when the first carcinomas appeared) was 0.22 carcinomas per mouse for the 600 and 60 µg/g groups vs. 0.44 for the 6 µg/g group (p less than 1 × 10^-6 in the Results text)
  • Dietary study: the 600 and 60 µg/g groups had the lowest carcinoma incidence rates (p = 0.0017)
  • Dietary study: the high beta-carotene diet gave a 25% protective effect against papilloma incidence (data not shown)
  • Topical study: in mice not treated with TPA, beta-carotene did not show significant tumor-promoting activity compared with the solvent THF
  • Topical study: in TPA-promoted mice, mean papilloma yield was 20 per mouse in controls vs. 10 per mouse with topical beta-carotene (p = 2.5 × 10^-7)
  • The lower papilloma yield persisted after beta-carotene dosing ended (20 weeks of age) through the end of the study
  • Skin treated with topical beta-carotene had an average 1.8-fold increase in RAR-alpha (n = 12 mice, p = 0.03) and a 6.9-fold increase in RAR-gamma (n = 11 mice, p = 0.03) compared with solvent-treated controls. RAR-beta levels were low and not statistically significantly different (n = 9 mice, p = 0.08).
• The authors' conclusion: The authors concluded that beta-carotene has chemopreventive activity against skin carcinoma formation, induces retinoic acid receptor expression, and fails to act as a tumor promoter in the two-stage model of skin tumorigenesis
• Limitations the authors state:
  • Unlike the authors' previous study, the intermediate 60 µg/g diet was also protective, and they do not know why the results varied
  • It is not established what mechanism caused the receptor increase, because there is no evidence that the epidermis can convert beta-carotene to retinoic acid

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Carcinogenesis, Clinical Trial, Lung Cancer.

Related studies

• Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke — X.D. Wang, C. Liu, et al. (1999)
• Initiation-promotion versus complete skin carcinogenesis in mice: importance of dark basal keratinocytes (stem cells) — T.J. Slaga, A.J. Klein-Szanto (1983)
• Phosphatide composition of normal, hyperplastic and malignant squamous epithelium — C. Carruthers (1966)
• NLRP3 promotes inflammation-induced skin cancer but is dispensable for asbestos-induced mesothelioma — M.T. Chow, J. Tschopp, et al. (2012)
• Beta carotene fails to prevent cancer in two major studies; CARET intervention stopped — K. Smigel (1996)
• The enigma of beta-carotene in carcinogenesis: what can be learned from animal studies — R.M. Russell (2004)

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