Skip to main content
NCBI home page
Gut logoLink to Gut
. 1994 Dec;35(12):1742–1746. doi: 10.1136/gut.35.12.1742

Divergent effects of epidermal growth factor and calcipotriol on human rectal cell proliferation.

M G Thomas 1, G R Brown 1, M R Alison 1, R C Williamson 1
PMCID: PMC1375263  PMID: 7829012

Abstract

Vitamin D may protect against colorectal cancer by reducing cell proliferation and inducing differentiation. By contrast, epidermal growth factor (EGF) stimulates cell proliferation and may encourage gastrointestinal mucosal healing. This study investigated the effect of a synthetic vitamin D analogue, calcipotriol, and EGF on human rectal epithelial cell proliferation in patients with familial adenomatous polyposis (FAP). In addition, a new technique to measure the cell cycle time is described. Sigmoidoscopic biopsy specimens were obtained from 14 patients with FAP. Tissue was established in organ culture, with or without the addition of EGF (n = 8), or calcipotriol (n = 6). Proliferation was determined using (a) metaphase arrest to measure the crypt cell production rate, (b) native mitotic index, and (c) the growth fraction using PC10 antibody. EGF receptor expression was shown using a polyclonal antibody AP12E. Calcipotriol reduced crypt cell production rate by 52% from mean (SEM) 5.29 (1.18) to 2.56 (0.80) cells/crypt/hour (p < 0.01) and EGF increased crypt cell production rate by 102% from 3.62 (0.59) to 7.33 (0.90) cells/crypt/hour (p < 0.05), and this tissue expressed the EGF receptor. The growth fraction was 48.40 (4.0)%, and the native mitotic index 1.08 (0.14)%. The cell cycle time was estimated as 94.5 hours and the time for mitosis as one hour. Thus, calcipotriol and EGF have divergent effects on human rectal mucosal proliferation.

Full text

PDF
1742

Images in this article

1744Figure 1
on p.1744
1745Figure 3
on p.1745

Selected References

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

  1. Anzano M. A., Rieman D., Prichett W., Bowen-Pope D. F., Greig R. Growth factor production by human colon carcinoma cell lines. Cancer Res. 1989 Jun 1;49(11):2898–2904. [PubMed] [Google Scholar]
  2. Appleton G. V., Wheeler E. E., Al-Mufti R., Challacombe D. N., Williamson R. C. Rectal hyperplasia after jejunoileal bypass for morbid obesity. Gut. 1988 Nov;29(11):1544–1548. doi: 10.1136/gut.29.11.1544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Appleton G. V., Wheeler E. E., Al-Mufti R., Challacombe D. N., Williamson R. C. Rectal hyperplasia after jejunoileal bypass for morbid obesity. Gut. 1988 Nov;29(11):1544–1548. doi: 10.1136/gut.29.11.1544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barsoum G. H., Hendrickse C., Winslet M. C., Youngs D., Donovan I. A., Neoptolemos J. P., Keighley M. R. Reduction of mucosal crypt cell proliferation in patients with colorectal adenomatous polyps by dietary calcium supplementation. Br J Surg. 1992 Jun;79(6):581–583. doi: 10.1002/bjs.1800790639. [DOI] [PubMed] [Google Scholar]
  5. Berger M. S., Gullick W. J., Greenfield C., Evans S., Addis B. J., Waterfield M. D. Epidermal growth factor receptors in lung tumours. J Pathol. 1987 Aug;152(4):297–307. doi: 10.1002/path.1711520408. [DOI] [PubMed] [Google Scholar]
  6. Binderup L., Bramm E. Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol. 1988 Mar 1;37(5):889–895. doi: 10.1016/0006-2952(88)90177-3. [DOI] [PubMed] [Google Scholar]
  7. Bleiberg H., Mainguet P., Galand P. Cell renewal in familial polyposis: comparison between polyps and adjacent healthy mucosa. Gastroenterology. 1972 Aug;63(2):240–245. [PubMed] [Google Scholar]
  8. Bodmer W. F., Bailey C. J., Bodmer J., Bussey H. J., Ellis A., Gorman P., Lucibello F. C., Murday V. A., Rider S. H., Scambler P. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. doi: 10.1038/328614a0. [DOI] [PubMed] [Google Scholar]
  9. Boman B. M., Levin B. Familial polyposis. Hosp Pract (Off Ed) 1986 May 15;21(5):155-65, 168, 170. [PubMed] [Google Scholar]
  10. Bradley S. J., Garfinkle G., Walker E., Salem R., Chen L. B., Steele G., Jr Increased expression of the epidermal growth factor receptor on human colon carcinoma cells. Arch Surg. 1986 Nov;121(11):1242–1247. doi: 10.1001/archsurg.121.11.1242. [DOI] [PubMed] [Google Scholar]
  11. Burt R. W., Bishop D. T., Cannon L. A., Dowdle M. A., Lee R. G., Skolnick M. H. Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N Engl J Med. 1985 Jun 13;312(24):1540–1544. doi: 10.1056/NEJM198506133122403. [DOI] [PubMed] [Google Scholar]
  12. Cannon-Albright L. A., Skolnick M. H., Bishop D. T., Lee R. G., Burt R. W. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med. 1988 Sep 1;319(9):533–537. doi: 10.1056/NEJM198809013190902. [DOI] [PubMed] [Google Scholar]
  13. Carpenter G. The biochemistry and physiology of the receptor-kinase for epidermal growth factor. Mol Cell Endocrinol. 1983 Jul;31(1):1–19. doi: 10.1016/0303-7207(83)90027-8. [DOI] [PubMed] [Google Scholar]
  14. Ferguson A., Sutherland A., MacDonald T. T., Allan F. Technique for microdissection and measurement in biopsies of human small intestine. J Clin Pathol. 1977 Nov;30(11):1068–1073. doi: 10.1136/jcp.30.11.1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goodlad R. A., Wilson T. J., Lenton W., Gregory H., McCullagh K. G., Wright N. A. Intravenous but not intragastric urogastrone-EGF is trophic to the intestine of parenterally fed rats. Gut. 1987 May;28(5):573–582. doi: 10.1136/gut.28.5.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Groden J., Thliveris A., Samowitz W., Carlson M., Gelbert L., Albertsen H., Joslyn G., Stevens J., Spirio L., Robertson M. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991 Aug 9;66(3):589–600. doi: 10.1016/0092-8674(81)90021-0. [DOI] [PubMed] [Google Scholar]
  17. Hall P. A., Levison D. A., Woods A. L., Yu C. C., Kellock D. B., Watkins J. A., Barnes D. M., Gillett C. E., Camplejohn R., Dover R. Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasms. J Pathol. 1990 Dec;162(4):285–294. doi: 10.1002/path.1711620403. [DOI] [PubMed] [Google Scholar]
  18. Herrera L., Kakati S., Gibas L., Pietrzak E., Sandberg A. A. Gardner syndrome in a man with an interstitial deletion of 5q. Am J Med Genet. 1986 Nov;25(3):473–476. doi: 10.1002/ajmg.1320250309. [DOI] [PubMed] [Google Scholar]
  19. Hill M. J., Morson B. C., Bussey H. J. Aetiology of adenoma--carcinoma sequence in large bowel. Lancet. 1978 Feb 4;1(8058):245–247. doi: 10.1016/s0140-6736(78)90487-7. [DOI] [PubMed] [Google Scholar]
  20. Huang S. A., Lin P. F., Fan D., Price J. E., Trujillo J. M., Chakrabarty S. Growth modulation by epidermal growth factor (EGF) in human colonic carcinoma cells: constitutive expression of the human EGF gene. J Cell Physiol. 1991 Aug;148(2):220–227. doi: 10.1002/jcp.1041480206. [DOI] [PubMed] [Google Scholar]
  21. Kinzler K. W., Nilbert M. C., Vogelstein B., Bryan T. M., Levy D. B., Smith K. J., Preisinger A. C., Hamilton S. R., Hedge P., Markham A. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science. 1991 Mar 15;251(4999):1366–1370. doi: 10.1126/science.1848370. [DOI] [PubMed] [Google Scholar]
  22. Konturek P. K., Brzozowski T., Konturek S. J., Dembiński A. Role of epidermal growth factor, prostaglandin, and sulfhydryls in stress-induced gastric lesions. Gastroenterology. 1990 Dec;99(6):1607–1615. doi: 10.1016/0016-5085(90)90464-c. [DOI] [PubMed] [Google Scholar]
  23. Kragballe K., Beck H. I., Søgaard H. Improvement of psoriasis by a topical vitamin D3 analogue (MC 903) in a double-blind study. Br J Dermatol. 1988 Aug;119(2):223–230. doi: 10.1111/j.1365-2133.1988.tb03204.x. [DOI] [PubMed] [Google Scholar]
  24. Kragballe K., Gjertsen B. T., De Hoop D., Karlsmark T., van de Kerkhof P. C., Larkö O., Nieboer C., Roed-Petersen J., Strand A., Tikjøb G. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet. 1991 Jan 26;337(8735):193–196. doi: 10.1016/0140-6736(91)92157-w. [DOI] [PubMed] [Google Scholar]
  25. Kragballe K. Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol (MC 903) Arch Dermatol. 1989 Dec;125(12):1647–1652. [PubMed] [Google Scholar]
  26. LIPKIN M., SHERLOCK P., BELL B. M. Generation time of epithelial cells in the human colon. Nature. 1962 Jul 14;195:175–177. doi: 10.1038/195175b0. [DOI] [PubMed] [Google Scholar]
  27. Leppert M., Dobbs M., Scambler P., O'Connell P., Nakamura Y., Stauffer D., Woodward S., Burt R., Hughes J., Gardner E. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science. 1987 Dec 4;238(4832):1411–1413. doi: 10.1126/science.3479843. [DOI] [PubMed] [Google Scholar]
  28. Lipkin M., Bell B., Sherlock P. CELL PROLIFERATION KINETICS IN THE GASTROINTESTINAL TRACT OF MAN. I. CELL RENEWAL IN COLON AND RECTUM. J Clin Invest. 1963 Jun;42(6):767–776. doi: 10.1172/JCI104769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lipkin M. Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. Cancer Res. 1988 Jan 15;48(2):235–245. [PubMed] [Google Scholar]
  30. Lipkin M., Newmark H. Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med. 1985 Nov 28;313(22):1381–1384. doi: 10.1056/NEJM198511283132203. [DOI] [PubMed] [Google Scholar]
  31. Lynch H. T., Smyrk T., Lanspa S. J., Marcus J. N., Kriegler M., Lynch J. F., Appelman H. D. Flat adenomas in a colon cancer-prone kindred. J Natl Cancer Inst. 1988 Apr 20;80(4):278–282. doi: 10.1093/jnci/80.4.278. [DOI] [PubMed] [Google Scholar]
  32. Nishisho I., Nakamura Y., Miyoshi Y., Miki Y., Ando H., Horii A., Koyama K., Utsunomiya J., Baba S., Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991 Aug 9;253(5020):665–669. doi: 10.1126/science.1651563. [DOI] [PubMed] [Google Scholar]
  33. Reeves J. R., Richards R. C., Cooke T. The effects of intracolonic EGF on mucosal growth and experimental carcinogenesis. Br J Cancer. 1991 Feb;63(2):223–226. doi: 10.1038/bjc.1991.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sarraf C. E., McCormick C. S., Brown G. R., Price Y. E., Hall P. A., Lane D. P., Alison M. R. Proliferating cell nuclear antigen immunolocalization in gastro-intestinal epithelia. Digestion. 1991;50(2):85–91. doi: 10.1159/000200744. [DOI] [PubMed] [Google Scholar]
  35. Scott R. J., Hall P. A., Haldane J. S., van Noorden S., Price Y., Lane D. P., Wright N. A. A comparison of immunohistochemical markers of cell proliferation with experimentally determined growth fraction. J Pathol. 1991 Oct;165(2):173–178. doi: 10.1002/path.1711650213. [DOI] [PubMed] [Google Scholar]
  36. Terpstra O. T., van Blankenstein M., Dees J., Eilers G. A. Abnormal pattern of cell proliferation in the entire colonic mucosa of patients with colon adenoma or cancer. Gastroenterology. 1987 Mar;92(3):704–708. doi: 10.1016/0016-5085(87)90021-7. [DOI] [PubMed] [Google Scholar]
  37. Thomas M. G., Tebbutt S., Williamson R. C. Vitamin D and its metabolites inhibit cell proliferation in human rectal mucosa and a colon cancer cell line. Gut. 1992 Dec;33(12):1660–1663. doi: 10.1136/gut.33.12.1660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Thomas M. G., Thomson J. P., Williamson R. C. Oral calcium inhibits rectal epithelial proliferation in familial adenomatous polyposis. Br J Surg. 1993 Apr;80(4):499–501. doi: 10.1002/bjs.1800800432. [DOI] [PubMed] [Google Scholar]
  39. Wright N. A., Pike C. M., Elia G. Ulceration induces a novel epidermal growth factor-secreting cell lineage in human gastrointestinal mucosa. Digestion. 1990;46 (Suppl 2):125–133. doi: 10.1159/000200375. [DOI] [PubMed] [Google Scholar]
  40. Wright N. A., Pike C., Elia G. Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells. Nature. 1990 Jan 4;343(6253):82–85. doi: 10.1038/343082a0. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES