Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1997 Jun;105(Suppl 4):985–988. doi: 10.1289/ehp.97105s4985

Roles of retinoids and their nuclear receptors in the development and prevention of upper aerodigestive tract cancers.

R Lotan 1
PMCID: PMC1470035  PMID: 9255592

Abstract

Vitamin A analogs (retinoids) suppress oral and lung carcinogenesis in animal models and prevent the development of second primary tumors in head, neck, and lung cancer patients. These effects result from changes in the expression of genes that regulate cell growth and differentiation. Retinoic acid receptors (RARs; -alpha, -beta, and -gamma) and retinoid X receptors (RXRs; -alpha, -beta, and, -gamma) are retinoid-activated transcription factors, which mediate effects of retinoids on gene expression. Therefore, alterations in receptor expression or function could interfere with the retinoid signaling pathway and thereby enhance cancer development. We found that the expression of RAR beta was suppressed in more than 50% of oral and lung premalignant lesions in individuals without cancer and in dysplastic lesions adjacent to cancer and in malignant oral and lung carcinomas. The expression of the other receptors was not different among normal, dysplastic, and malignant oral tissues. However, the expression of RAR gamma and RXR beta was somewhat decreased in lung cancers. These results show that RAR beta expression is lost at early stages of carcinogenesis in the aerodigestive tract and support the hypothesis that the loss of RAR beta expression may facilitate the development of some of these cancers.

Full text

PDF
986

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auerbach O., Hammond E. C., Garfinkel L. Changes in bronchial epithelium in relation to cigarette smoking, 1955-1960 vs. 1970-1977. N Engl J Med. 1979 Feb 22;300(8):381–385. doi: 10.1056/NEJM197902223000801. [DOI] [PubMed] [Google Scholar]
  2. Bartsch D., Boye B., Baust C., zur Hausen H., Schwarz E. Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor beta gene in non-tumorigenic and tumorigenic HeLa hybrid cells. EMBO J. 1992 Jun;11(6):2283–2291. doi: 10.1002/j.1460-2075.1992.tb05287.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chambon P. The retinoid signaling pathway: molecular and genetic analyses. Semin Cell Biol. 1994 Apr;5(2):115–125. doi: 10.1006/scel.1994.1015. [DOI] [PubMed] [Google Scholar]
  4. Clifford J. L., Petkovich M., Chambon P., Lotan R. Modulation by retinoids of mRNA levels for nuclear retinoic acid receptors in murine melanoma cells. Mol Endocrinol. 1990 Oct;4(10):1546–1555. doi: 10.1210/mend-4-10-1546. [DOI] [PubMed] [Google Scholar]
  5. De Luca L. M. Retinoids and their receptors in differentiation, embryogenesis, and neoplasia. FASEB J. 1991 Nov;5(14):2924–2933. [PubMed] [Google Scholar]
  6. Gebert J. F., Moghal N., Frangioni J. V., Sugarbaker D. J., Neel B. G. High frequency of retinoic acid receptor beta abnormalities in human lung cancer. Oncogene. 1991 Oct;6(10):1859–1868. [PubMed] [Google Scholar]
  7. Geradts J., Chen J. Y., Russell E. K., Yankaskas J. R., Nieves L., Minna J. D. Human lung cancer cell lines exhibit resistance to retinoic acid treatment. Cell Growth Differ. 1993 Oct;4(10):799–809. [PubMed] [Google Scholar]
  8. Halpern M. T., Gillespie B. W., Warner K. E. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst. 1993 Mar 17;85(6):457–464. doi: 10.1093/jnci/85.6.457. [DOI] [PubMed] [Google Scholar]
  9. Hong W. K., Endicott J., Itri L. M., Doos W., Batsakis J. G., Bell R., Fofonoff S., Byers R., Atkinson E. N., Vaughan C. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med. 1986 Dec 11;315(24):1501–1505. doi: 10.1056/NEJM198612113152401. [DOI] [PubMed] [Google Scholar]
  10. Hong W. K., Lippman S. M., Itri L. M., Karp D. D., Lee J. S., Byers R. M., Schantz S. P., Kramer A. M., Lotan R., Peters L. J. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990 Sep 20;323(12):795–801. doi: 10.1056/NEJM199009203231205. [DOI] [PubMed] [Google Scholar]
  11. Houle B., Leduc F., Bradley W. E. Implication of RARB in epidermoid (Squamous) lung cancer. Genes Chromosomes Cancer. 1991 Sep;3(5):358–366. doi: 10.1002/gcc.2870030506. [DOI] [PubMed] [Google Scholar]
  12. Houle B., Rochette-Egly C., Bradley W. E. Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):985–989. doi: 10.1073/pnas.90.3.985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hu L., Crowe D. L., Rheinwald J. G., Chambon P., Gudas L. J. Abnormal expression of retinoic acid receptors and keratin 19 by human oral and epidermal squamous cell carcinoma cell lines. Cancer Res. 1991 Aug 1;51(15):3972–3981. [PubMed] [Google Scholar]
  14. Jetten A. M., Kim J. S., Sacks P. G., Rearick J. I., Lotan D., Hong W. K., Lotan R. Inhibition of growth and squamous-cell differentiation markers in cultured human head and neck squamous carcinoma cells by beta-all-trans retinoic acid. Int J Cancer. 1990 Jan 15;45(1):195–202. doi: 10.1002/ijc.2910450135. [DOI] [PubMed] [Google Scholar]
  15. Kato S., Mano H., Kumazawa T., Yoshizawa Y., Kojima R., Masushige S. Effect of retinoid status on alpha, beta and gamma retinoic acid receptor mRNA levels in various rat tissues. Biochem J. 1992 Sep 15;286(Pt 3):755–760. doi: 10.1042/bj2860755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kim J. S., Steck P. A., Gallick G. E., Lee J. S., Blick M., Hong W. K., Lotan R. Suppression by retinoic acid of epidermal growth factor receptor autophosphorylation and glycosylation in cultured human head and neck squamous carcinoma cells. J Natl Cancer Inst Monogr. 1992;(13):101–110. [PubMed] [Google Scholar]
  17. Lippman S. M., Batsakis J. G., Toth B. B., Weber R. S., Lee J. J., Martin J. W., Hays G. L., Goepfert H., Hong W. K. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med. 1993 Jan 7;328(1):15–20. doi: 10.1056/NEJM199301073280103. [DOI] [PubMed] [Google Scholar]
  18. Lippman S. M., Benner S. E., Hong W. K. Cancer chemoprevention. J Clin Oncol. 1994 Apr;12(4):851–873. doi: 10.1200/JCO.1994.12.4.851. [DOI] [PubMed] [Google Scholar]
  19. Lotan R., Clifford J. L. Nuclear receptors for retinoids: mediators of retinoid effects on normal and malignant cells. Biomed Pharmacother. 1991;45(4-5):145–156. doi: 10.1016/0753-3322(91)90102-y. [DOI] [PubMed] [Google Scholar]
  20. Lotan R., Lotan D., Sacks P. G. Inhibition of tumor cell growth by retinoids. Methods Enzymol. 1990;190:100–110. doi: 10.1016/0076-6879(90)90014-r. [DOI] [PubMed] [Google Scholar]
  21. Lotan R., Sacks P. G., Lotan D., Hong W. K. Differential effects of retinoic acid on the in vitro growth and cell-surface glycoconjugates of 2 human head and neck squamous-cell carcinomas. Int J Cancer. 1987 Aug 15;40(2):224–229. doi: 10.1002/ijc.2910400217. [DOI] [PubMed] [Google Scholar]
  22. Lotan R. Squamous cell differentiation markers in normal, premalignant, and malignant epithelium: effects of retinoids. J Cell Biochem Suppl. 1993;17F:167–174. doi: 10.1002/jcb.240531024. [DOI] [PubMed] [Google Scholar]
  23. Lotan R., Xu X. C., Lippman S. M., Ro J. Y., Lee J. S., Lee J. J., Hong W. K. Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med. 1995 May 25;332(21):1405–1410. doi: 10.1056/NEJM199505253322103. [DOI] [PubMed] [Google Scholar]
  24. Lubin J. H., Blot W. J. Lung cancer and smoking cessation: patterns of risk. J Natl Cancer Inst. 1993 Mar 17;85(6):422–423. doi: 10.1093/jnci/85.6.422. [DOI] [PubMed] [Google Scholar]
  25. Nervi C., Vollberg T. M., George M. D., Zelent A., Chambon P., Jetten A. M. Expression of nuclear retinoic acid receptors in normal tracheobronchial cells and in lung carcinoma cells. Exp Cell Res. 1991 Jul;195(1):163–170. doi: 10.1016/0014-4827(91)90512-s. [DOI] [PubMed] [Google Scholar]
  26. Oridate N., Lotan R., Lotan D. Reconstituted basement membrane (Matrigel): a useful semisolid medium for growth of tumor cell colonies. In Vitro Cell Dev Biol Anim. 1996 Apr;32(4):192–193. doi: 10.1007/BF02722944. [DOI] [PubMed] [Google Scholar]
  27. Pastorino U., Infante M., Maioli M., Chiesa G., Buyse M., Firket P., Rosmentz N., Clerici M., Soresi E., Valente M. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol. 1993 Jul;11(7):1216–1222. doi: 10.1200/JCO.1993.11.7.1216. [DOI] [PubMed] [Google Scholar]
  28. Pfahl M. Vertebrate receptors: molecular biology, dimerization and response elements. Semin Cell Biol. 1994 Apr;5(2):95–103. doi: 10.1006/scel.1994.1013. [DOI] [PubMed] [Google Scholar]
  29. Poddar S., Hong W. K., Thacher S. M., Lotan R. Retinoic acid suppression of squamous differentiation in human head-and-neck squamous carcinoma cells. Int J Cancer. 1991 May 10;48(2):239–247. doi: 10.1002/ijc.2910480215. [DOI] [PubMed] [Google Scholar]
  30. SLAUGHTER D. P., SOUTHWICK H. W., SMEJKAL W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953 Sep;6(5):963–968. doi: 10.1002/1097-0142(195309)6:5<963::aid-cncr2820060515>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  31. Shklar G., Schwartz J., Grau D., Trickler D. P., Wallace K. D. Inhibition of hamster buccal pouch carcinogenesis by 13-cis-retinoic acid. Oral Surg Oral Med Oral Pathol. 1980 Jul;50(1):45–52. doi: 10.1016/0030-4220(80)90330-8. [DOI] [PubMed] [Google Scholar]
  32. Shopland D. R., Eyre H. J., Pechacek T. F. Smoking-attributable cancer mortality in 1991: is lung cancer now the leading cause of death among smokers in the United States? J Natl Cancer Inst. 1991 Aug 21;83(16):1142–1148. doi: 10.1093/jnci/83.16.1142. [DOI] [PubMed] [Google Scholar]
  33. Sporn M. B., Newton D. L. Chemoprevention of cancer with retinoids. Fed Proc. 1979 Oct;38(11):2528–2534. [PubMed] [Google Scholar]
  34. Strong M. S., Incze J., Vaughan C. W. Field cancerization in the aerodigestive tract--its etiology, manifestation, and significance. J Otolaryngol. 1984 Feb;13(1):1–6. [PubMed] [Google Scholar]
  35. Verma A. K., Shoemaker A., Simsiman R., Denning M., Zachman R. D. Expression of retinoic acid nuclear receptors and tissue transglutaminase is altered in various tissues of rats fed a vitamin A-deficient diet. J Nutr. 1992 Nov;122(11):2144–2152. doi: 10.1093/jn/122.11.2144. [DOI] [PubMed] [Google Scholar]
  36. Vokes E. E., Weichselbaum R. R., Lippman S. M., Hong W. K. Head and neck cancer. N Engl J Med. 1993 Jan 21;328(3):184–194. doi: 10.1056/NEJM199301213280306. [DOI] [PubMed] [Google Scholar]
  37. Wingo P. A., Tong T., Bolden S. Cancer statistics, 1995. CA Cancer J Clin. 1995 Jan-Feb;45(1):8–30. doi: 10.3322/canjclin.45.1.8. [DOI] [PubMed] [Google Scholar]
  38. Xu X. C., Clifford J. L., Hong W. K., Lotan R. Detection of nuclear retinoic acid receptor mRNA in histological tissue sections using nonradioactive in situ hybridization histochemistry. Diagn Mol Pathol. 1994 Jun;3(2):122–131. doi: 10.1097/00019606-199406000-00009. [DOI] [PubMed] [Google Scholar]
  39. Xu X. C., Ro J. Y., Lee J. S., Shin D. M., Hong W. K., Lotan R. Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues. Cancer Res. 1994 Jul 1;54(13):3580–3587. [PubMed] [Google Scholar]
  40. Xu X. C., Zile M. H., Lippman S. M., Lee J. S., Lee J. J., Hong W. K., Lotan R. Anti-retinoic acid (RA) antibody binding to human premalignant oral lesions, which occurs less frequently than binding to normal tissue, increases after 13-cis-RA treatment in vivo and is related to RA receptor beta expression. Cancer Res. 1995 Dec 1;55(23):5507–5511. [PubMed] [Google Scholar]
  41. Zelent A., Mendelsohn C., Kastner P., Krust A., Garnier J. M., Ruffenach F., Leroy P., Chambon P. Differentially expressed isoforms of the mouse retinoic acid receptor beta generated by usage of two promoters and alternative splicing. EMBO J. 1991 Jan;10(1):71–81. doi: 10.1002/j.1460-2075.1991.tb07922.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Zhang X. K., Liu Y., Lee M. O., Pfahl M. A specific defect in the retinoic acid response associated with human lung cancer cell lines. Cancer Res. 1994 Nov 1;54(21):5663–5669. [PubMed] [Google Scholar]
  43. Zou C. P., Clifford J. L., Xu X. C., Sacks P. G., Chambon P., Hong W. K., Lotan R. Modulation by retinoic acid (RA) of squamous cell differentiation, cellular RA-binding proteins, and nuclear RA receptors in human head and neck squamous cell carcinoma cell lines. Cancer Res. 1994 Oct 15;54(20):5479–5487. [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES