755
apparently facilitates
the processes
leading
to
colon
23. Gori, J. B. Cancer Res. 1975, 35, 3432. 24. Cruse, J. P., Lewin, M. R., Ferulano, G. P., Clark, C. G. Nature, 1978, 276,
cancer.
822.
P. C. is a Rhodes Scholar and of the Rhodes Trust, Oxford.
gratefully acknowledges
the support
Requests for reprints should be addressed to P. C. REFERENCES 1 Hill, M. J., Morson, B. C., Bussey, H. J. R. Lancet, 1978, i, 245. 2 Peto, R. in Origins of Human Cancer (edited by H. Hiatt); Book C, p. 1403.
25. 26. 27. 28. 29.
30. 31. 32. 33. 34. 35. 36. 37. 38. 39.
Broitman, S. A. et al. Cancer, 1977, 40, 2455. Reddy, B. S., et al. Proc. Soc. exp. Biol. Med. 1976, 151, 237. Nigro, N. D. et al. J. natn. Cancer Inst. 1975, 54, 439. Bansal, B. R., Rhoads, J. E., Bansal, S. C. Cancer Res. 1978, 38, 3293. Reddy, B. S., Nansawa, T., Weisburger, J. H. J. natn. Cancer Inst. 1976,
57, 567. Reddy, B. S., Weisburger, J. H., Wynder, E. L. ibid. 1974, 52, 507. Nigro, N. D. et al. Dis. Colon Rectum, 1973, 16, 438. Narisawa, T., et al. J. natn. Cancer Inst. 1974, 53, 1093. Carroll, K. K., Khor, H. T. Progr. biochem. Pharmac. 1975, 10, 308.
McCance and Widdowson’s The Composition of Foods (edited by A. A. Paul and D. A. T. Southgate). H. M. Stationery Office, 1978. 10 Drasar, B. S., Irving, D. Br. J. Cancer, 1973, 27, 167. 11. Royal College of Physicians Report. J. R. Coll. Physns. 1976, 10, 1. 12. Bronte-Stewart, B., Keys, A., Brock, J. F. Lancet, 1955, ii, 1103. 13. Reddy, B. S., Wynder, E. L. Cancer, 1977, 39, 2533.
Mathews, J. D., Feery, B. J. Lancet, 1978, ii, 1212. Inbar, M., Shinitsky, M. Proc. natn. Acad. Sci. U.S.A., 1974, 71, 4229 Pratt, C. B., et al. Cancer, 1977, 40, 2464. Selikoff, J. J., Churg, J., Hammond, E. C. J. Am. med. Ass. 1964, 188, 22. Vobecky, J., et al. Gastroenterology, 1978, 75, 221. Sugimura, T., et al. in Origins of Human Cancer (edited by H. Hiatt); p. 1561. New York, 1977. 40. Bruce, W. R., et al. ibid. p. 1641. 41. Morson, B. C. Cancer, 1974, 34, 845. 42. Aries, V. C. et al. Gut, 1969, 10, 334. 43. Hill, M. J., Crowther, J. S., Drasar, B. S., Hawksworth, G., Aries, V., Wilhams, R. E. O. Lancet, 1971, i, 95. 44. Murray, W. R., et al. Br. J. Surg. (in the press). 45. Mastromarino, A. J., Reddy, B. S., Wynder, E. L. Cancer Res. 1978, 38,
14. 15 16 17 18. 19
Reddy, B. S. Cancer, 1976, 38, 1094. Reddy, B. S., Martin, C. W., Wynder, E. L. Cancer Res. 1977, 37, 1697. Core, S. K , Watne, A. L. Fedn. Proc. 1974, 33, 260. Salyers, A. A., et al. S. Afr. Med. J. 1977, 51, 823. Slater, G. G., Alfin-Slater, R. B. Fedn Proc. 1978, 37, 630. McGandy, R. B., Hegsted, D. M. in The Role of Fats in Human Nutrition (edited by A. J. Vergroesen); p. 211. New York, 1975. 20. Rose, G., Blackburn, H., Keys, A., Taylor, H. L., Kannel, W. B., Paul, O., Reid, D. D., Stamler, J. Lancet, 1974, i, 181. 21. Bjelke, E ibid. 1974, i, 1116. 22. Cutler, C. J., Devesa, S. A. Host Environment Interactions in the Etiology of Cancer in Man. p. 14. I.A.R.C., Lyon, 1974.
4458. 46. Sabme, J. R. Cholesterol. New York, 1977. 47. Hradec, J. Prog. Biochem. Pharmac. 1975, 10, 197. 48. Nair, P., Kritchevsky, D. (editors.) The Bile Acids; vol. 1 and 2. New 1973. 49. Dietschy, J. M. Fedn. Proc. 1967, 26, 1589. 50. Hofmann, A. F. Gastroenterology, 1967, 52, 752. 51. Dietschy, J. M., Wilson, J. D. New Engl. J. Med. 1970, 282, 1179. 52. Dietschy, J. M., Wilson, J. D. ibid. 1970, 282, 1241. 53. Sinclair, H. M. Personal communication. 54. Buell, P., Dunn, J. E. Cancer, 1965, 18, 656. 55. Philips, R. L. Science, 1974, 183, 471.
RELATION BETWEEN AFLATOXIN, HEPATITIS-B VIRUS, AND HEPATOCELLULAR CARCINOMA
all been
New York, 1977. 3 Hill, M. J. Crit. Rev. Toxicol. 1975, 4, 31. 4. Wynder, E. L., Reddy, B. S. in Nutrition and Cancer
(edited by M. Winik);
55. New York, 1977. 5 Berenblum, I. J. natn. Cancer Inst. 1978, 60, 723. 6 Miller, E. C Cancer Res. 1978, 38, 1479. 7 Wynder, E. L , Shigematsu, T. Cancer, 1967, 20, 1520. 8. Hill, M. J. Digestion, 1974, 11, 289. p
9
York,
implicated as xtiological agents.6 The two most important factors seem to be hepatitis-B virus (H.B.v.) and the mycotoxin, aflatoxin.
LARRY I. LUTWICK HEPATITIS-B VIRUS AND HEPATOMA
Division
of Infectious Diseases, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, U.S.A.
A new role is postulated for aflatoxin in the production of hepatocellular carcinoma. Rather than acting as a primary carcinogen, as it seems to do in animals, it is suggested that aflatoxin suppresses cell-mediated immunity. This effect on the immune system would allow the hepatitis-B virus, highly endemic in certain populations, to maintain itself more easily in the liver, to produce more chronic infection and cirrhosis, and in the long term to lead to a high incidence of hepatocellular carcinoma.
Summary
H.B.v.-associated antigens and antibodies are significantly more common in patients with hepatoma than in the general population2,5,7-9 or in age and sex matched controls with and without other cancers. to Studies in various parts of the world have shown that H.B.v. is closely associated with a predisposition to hepatic malignancy (table I), but the exact role of the virus is not clear. TABLE I-ASSOCIATION OF H.B.V. WITH HEPATOMA
INTRODUCTION
PRIMARY
pecially
hepatocellular carcinoma (hepatoma) is esin several major population groups. In
common
parts of Africa it is so common that right-sided abdominal pain and massive hepatomegaly are regarded as diagnostic.’ Because of its high incidence in these large population groups it is thought to be the most common cancer in man.2 Although hepatoma has not been a common malignancy in the U.S.A. and Western Europe, its incidence seems to be increasing. 3-5 Genetic factors, alcoholism, malnutrition, iron overload, parasites, and ’. anous natural and synthetic drugs and chemicals have some
*HB, Ag=hepamis-B surface antigen ; anti-HBantibody to tis-B surface; anti-HB=antibody to hepatitis-B core antigen. tControl group age and sex matched with other cancer or no
hepaticancer.
756
Possibly H.B.v., in producing cirrhosis, is only an indirect factor in malignant change, with cancer being a product of chronic regeneration." This presumably is the mechanism which accounts for the cases of hepatoma associated with alcoholic cirrhosis. 25% of H.B.v.associated hepatomas, however, do not demonstrate fibrosis histologically."I Two recent discoveries suggest that the virus may play a more direct role in oncogenesis. Alexander et al. 12 have derived a human hepatoma cell-line which produces H.B.v. surface antigen (HBs Ag) in the cell culture supernatant. Despite many attempts by several workers, the line does not produce the internal (core) antigen of the virus. One explanation for this finding is that only part of the H.B.v. genome is present in the cell-line and integrated into the cell genome. Lutwick and Robinson13 found that some of the D.N.A. extracted from a chronically infected liver, which was homologous with the H.B.V. b.N.A., had a much higher molecular weight than the small circular H.B.V. D.N.A. The most likely explanation for this finding is that part of the viral genome was combined with the liver-cell D.N.A. Oncogenesis by a D.N.A. virus requires integration of viral D.N.A. into the cellular D.N.A. 14
aflatoxin is associated with hepatoma. There are no reports of a low frequency of hepatoma in areas of high aflatoxin exposure to counterbalance these data. If aflatoxin ingestion were a major factor in predisposition to hepatoma, one would expect the risk of cancer to be higher for H.B.v. carriers from Mozambique than from U.S.A. (with a low intake of aflatoxin). But Prince21 estimated that the risks of hepatoma development in H.B.V. carriers in Mozambique and the U.S.A.
TABLE III-RISK OF DEVELOPMENT OF HEPATOMA IN MALE
HB
apparently facilitates
the processes
leading
to
colon
23. Gori, J. B. Cancer Res. 1975, 35, 3432. 24. Cruse, J. P., Lewin, M. R., Ferulano, G. P., Clark, C. G. Nature, 1978, 276,
cancer.
822.
P. C. is a Rhodes Scholar and of the Rhodes Trust, Oxford.
gratefully acknowledges
the support
Requests for reprints should be addressed to P. C. REFERENCES 1 Hill, M. J., Morson, B. C., Bussey, H. J. R. Lancet, 1978, i, 245. 2 Peto, R. in Origins of Human Cancer (edited by H. Hiatt); Book C, p. 1403.
25. 26. 27. 28. 29.
30. 31. 32. 33. 34. 35. 36. 37. 38. 39.
Broitman, S. A. et al. Cancer, 1977, 40, 2455. Reddy, B. S., et al. Proc. Soc. exp. Biol. Med. 1976, 151, 237. Nigro, N. D. et al. J. natn. Cancer Inst. 1975, 54, 439. Bansal, B. R., Rhoads, J. E., Bansal, S. C. Cancer Res. 1978, 38, 3293. Reddy, B. S., Nansawa, T., Weisburger, J. H. J. natn. Cancer Inst. 1976,
57, 567. Reddy, B. S., Weisburger, J. H., Wynder, E. L. ibid. 1974, 52, 507. Nigro, N. D. et al. Dis. Colon Rectum, 1973, 16, 438. Narisawa, T., et al. J. natn. Cancer Inst. 1974, 53, 1093. Carroll, K. K., Khor, H. T. Progr. biochem. Pharmac. 1975, 10, 308.
McCance and Widdowson’s The Composition of Foods (edited by A. A. Paul and D. A. T. Southgate). H. M. Stationery Office, 1978. 10 Drasar, B. S., Irving, D. Br. J. Cancer, 1973, 27, 167. 11. Royal College of Physicians Report. J. R. Coll. Physns. 1976, 10, 1. 12. Bronte-Stewart, B., Keys, A., Brock, J. F. Lancet, 1955, ii, 1103. 13. Reddy, B. S., Wynder, E. L. Cancer, 1977, 39, 2533.
Mathews, J. D., Feery, B. J. Lancet, 1978, ii, 1212. Inbar, M., Shinitsky, M. Proc. natn. Acad. Sci. U.S.A., 1974, 71, 4229 Pratt, C. B., et al. Cancer, 1977, 40, 2464. Selikoff, J. J., Churg, J., Hammond, E. C. J. Am. med. Ass. 1964, 188, 22. Vobecky, J., et al. Gastroenterology, 1978, 75, 221. Sugimura, T., et al. in Origins of Human Cancer (edited by H. Hiatt); p. 1561. New York, 1977. 40. Bruce, W. R., et al. ibid. p. 1641. 41. Morson, B. C. Cancer, 1974, 34, 845. 42. Aries, V. C. et al. Gut, 1969, 10, 334. 43. Hill, M. J., Crowther, J. S., Drasar, B. S., Hawksworth, G., Aries, V., Wilhams, R. E. O. Lancet, 1971, i, 95. 44. Murray, W. R., et al. Br. J. Surg. (in the press). 45. Mastromarino, A. J., Reddy, B. S., Wynder, E. L. Cancer Res. 1978, 38,
14. 15 16 17 18. 19
Reddy, B. S. Cancer, 1976, 38, 1094. Reddy, B. S., Martin, C. W., Wynder, E. L. Cancer Res. 1977, 37, 1697. Core, S. K , Watne, A. L. Fedn. Proc. 1974, 33, 260. Salyers, A. A., et al. S. Afr. Med. J. 1977, 51, 823. Slater, G. G., Alfin-Slater, R. B. Fedn Proc. 1978, 37, 630. McGandy, R. B., Hegsted, D. M. in The Role of Fats in Human Nutrition (edited by A. J. Vergroesen); p. 211. New York, 1975. 20. Rose, G., Blackburn, H., Keys, A., Taylor, H. L., Kannel, W. B., Paul, O., Reid, D. D., Stamler, J. Lancet, 1974, i, 181. 21. Bjelke, E ibid. 1974, i, 1116. 22. Cutler, C. J., Devesa, S. A. Host Environment Interactions in the Etiology of Cancer in Man. p. 14. I.A.R.C., Lyon, 1974.
4458. 46. Sabme, J. R. Cholesterol. New York, 1977. 47. Hradec, J. Prog. Biochem. Pharmac. 1975, 10, 197. 48. Nair, P., Kritchevsky, D. (editors.) The Bile Acids; vol. 1 and 2. New 1973. 49. Dietschy, J. M. Fedn. Proc. 1967, 26, 1589. 50. Hofmann, A. F. Gastroenterology, 1967, 52, 752. 51. Dietschy, J. M., Wilson, J. D. New Engl. J. Med. 1970, 282, 1179. 52. Dietschy, J. M., Wilson, J. D. ibid. 1970, 282, 1241. 53. Sinclair, H. M. Personal communication. 54. Buell, P., Dunn, J. E. Cancer, 1965, 18, 656. 55. Philips, R. L. Science, 1974, 183, 471.
RELATION BETWEEN AFLATOXIN, HEPATITIS-B VIRUS, AND HEPATOCELLULAR CARCINOMA
all been
New York, 1977. 3 Hill, M. J. Crit. Rev. Toxicol. 1975, 4, 31. 4. Wynder, E. L., Reddy, B. S. in Nutrition and Cancer
(edited by M. Winik);
55. New York, 1977. 5 Berenblum, I. J. natn. Cancer Inst. 1978, 60, 723. 6 Miller, E. C Cancer Res. 1978, 38, 1479. 7 Wynder, E. L , Shigematsu, T. Cancer, 1967, 20, 1520. 8. Hill, M. J. Digestion, 1974, 11, 289. p
9
York,
implicated as xtiological agents.6 The two most important factors seem to be hepatitis-B virus (H.B.v.) and the mycotoxin, aflatoxin.
LARRY I. LUTWICK HEPATITIS-B VIRUS AND HEPATOMA
Division
of Infectious Diseases, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, U.S.A.
A new role is postulated for aflatoxin in the production of hepatocellular carcinoma. Rather than acting as a primary carcinogen, as it seems to do in animals, it is suggested that aflatoxin suppresses cell-mediated immunity. This effect on the immune system would allow the hepatitis-B virus, highly endemic in certain populations, to maintain itself more easily in the liver, to produce more chronic infection and cirrhosis, and in the long term to lead to a high incidence of hepatocellular carcinoma.
Summary
H.B.v.-associated antigens and antibodies are significantly more common in patients with hepatoma than in the general population2,5,7-9 or in age and sex matched controls with and without other cancers. to Studies in various parts of the world have shown that H.B.v. is closely associated with a predisposition to hepatic malignancy (table I), but the exact role of the virus is not clear. TABLE I-ASSOCIATION OF H.B.V. WITH HEPATOMA
INTRODUCTION
PRIMARY
pecially
hepatocellular carcinoma (hepatoma) is esin several major population groups. In
common
parts of Africa it is so common that right-sided abdominal pain and massive hepatomegaly are regarded as diagnostic.’ Because of its high incidence in these large population groups it is thought to be the most common cancer in man.2 Although hepatoma has not been a common malignancy in the U.S.A. and Western Europe, its incidence seems to be increasing. 3-5 Genetic factors, alcoholism, malnutrition, iron overload, parasites, and ’. anous natural and synthetic drugs and chemicals have some
*HB, Ag=hepamis-B surface antigen ; anti-HBantibody to tis-B surface; anti-HB=antibody to hepatitis-B core antigen. tControl group age and sex matched with other cancer or no
hepaticancer.
756
Possibly H.B.v., in producing cirrhosis, is only an indirect factor in malignant change, with cancer being a product of chronic regeneration." This presumably is the mechanism which accounts for the cases of hepatoma associated with alcoholic cirrhosis. 25% of H.B.v.associated hepatomas, however, do not demonstrate fibrosis histologically."I Two recent discoveries suggest that the virus may play a more direct role in oncogenesis. Alexander et al. 12 have derived a human hepatoma cell-line which produces H.B.v. surface antigen (HBs Ag) in the cell culture supernatant. Despite many attempts by several workers, the line does not produce the internal (core) antigen of the virus. One explanation for this finding is that only part of the H.B.v. genome is present in the cell-line and integrated into the cell genome. Lutwick and Robinson13 found that some of the D.N.A. extracted from a chronically infected liver, which was homologous with the H.B.V. b.N.A., had a much higher molecular weight than the small circular H.B.V. D.N.A. The most likely explanation for this finding is that part of the viral genome was combined with the liver-cell D.N.A. Oncogenesis by a D.N.A. virus requires integration of viral D.N.A. into the cellular D.N.A. 14
aflatoxin is associated with hepatoma. There are no reports of a low frequency of hepatoma in areas of high aflatoxin exposure to counterbalance these data. If aflatoxin ingestion were a major factor in predisposition to hepatoma, one would expect the risk of cancer to be higher for H.B.v. carriers from Mozambique than from U.S.A. (with a low intake of aflatoxin). But Prince21 estimated that the risks of hepatoma development in H.B.V. carriers in Mozambique and the U.S.A.
TABLE III-RISK OF DEVELOPMENT OF HEPATOMA IN MALE
HB
