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Acknowledgements We are grateful to Jean Bain for assistance. The experimental work upon which formulation of this hypothesis depended was supported by grants from the Wellcome Trust, London, the Edna McConnell Clark Foundation, New York, and the UNDP/World Bank/WHO Special Programme ibr Research and Training in Tropical Diseases, Geneva.

References 1 2 3 4

Warren, K. S. (1973) Helm. Abstr. Ser. A 42, 590-633 Warren, K. S. (1975)Bull. N. Y. Acad. Med. 51,545-555 Von Lichtenberg, F. (1964) Am. J. Pathol. 45, 75-93 Doenhof[,M., Musallam, R., Bain, J. and McGregor, A. (1979) Am.J. Trop. Med. Hyg. (1979) 28, 260-273 5 Byram,J. E. and Lichtenberg, F. yon (197.7)Am. J. Trop. Med. Htg. 26, 944-956 6 Dunne, D. W., Lucas, S., Bickle, Q., Pearson, S., Madgwick, L., Bain,

J. and Doenhoff, M. (1981) Trans. Roy. Soc. Trop. Med. Hyg. 75, 54-71 7 Doenhoff, M., Harrison, R., Sabah, A., Murare, H., Dunne, D. and Hassounah, O. (1982) In Animal Models in Parasitology (Owen, D., ed.), 155-169, Macmillan, Oxford 8 Doenhoff, M.J., Hassounah, O., Murare, H., Bain, J. and Lucas, S. (1985) Trans. Roy. So¢. Trop. Med. Hyg. (in press) 9 Doenhoff, M., Musallam, R., Bain, J. and McGregor, A. (1978) Immunology 35, 771-778 10 Dunne, D. W., Hassounah, O., Musanam, R., Lucas, S., Pepys, M. B., Bahz, M. and Doenhoff, M. (1983) ParasiteImmunoL 5, 47-60 11 Doenhoff, M. J., Pearson, S., Dunne, D. W., Bickle, Q., Lucas, S., Bain, J., Musallam, R. and Hassounah, O. (1981) Trans. Roy. Soc. Trop. Med. Hyg. 75, 41-53 12 Smithers, S. R. and Doenhoff, M. J. (1982) In Immunology of Parasitic Infections (2nd ed.) (Cohen, S. and Warren, K. S., eds) 527-602, Blackwell Scientific, Oxford 13 Fidler, I. J., Gersten, D. M., Kripke, M. L. (1979) Cancer Res. 39, 3816-3821 14 Karpatkin, S. and Pearlstein, E. (1981) Ann. Int. Med. 95, 636-641

New directions in research

Ultraviolet light and skin cancer Skin cancer is the most common malignancy in man. In the United States more than 400 000 cases of nonmelanoma skin cancer and approximately 22 000 cases of melanoma are diagnosed annually 1. Excessive exposure to sunlight is the major etiologic factor in the development of basal cell carcinomas (BCC's) and squamous cell carcinomas (SCC's) and, possibly, some malignant melanomas. Skin cancer is particularly prone to occur in fair skinned individuals, with light eye and hair color, who sunburn easily, but tan poorly. Most BCC's and SCC's occur on sun exposed areas especially of the head, neck, and upper limbs. The most carcinogenic portion of the ultraviolet light (UVL) spectrum is in the ultraviolet light-B (UV-B) or sunburn range of 290 to 320 nm wavelength. U V L carcinogenesis is a complex process which is not completely understood. At least two distinct mechanisms are involved 2. Firstly, chronic exposure of animals to U V L shows that it acts both as a tumor initiator and promoter upon epidermal cells. Secondly, it may impair the body's immune responses to the altered epidermal cells. Experiments in albino mice have demonstrated that U V L carcinogenesis is a continuous cumulative process that begins with the initial exposure and progresses with each subsequent exposure 3. A possible mechanism is the photochemical conversion of sterols to carcinogenic substances such as cholesterol-5a, 6a-epoxide 4. Induction of the polyamine-biosynthetic enzyme ornithine decarboxylase (ODC) may be an obligatory step in the carcinogenic process 5. Chronic U V L exposure causes D N A damage. Defective repair of such injury leads to malignant transformation 6. Deficiency of an enzyme (UV-endonuclease) is responsible for defective repair of U V L damaged D N A in patients with xeroderma pigmentosum, a rare genetic disorder, in which skin cancers are extremely common 7. In addition to its direct carcinogenic effects U V L also causes immunosuppression, which permits the survival and growth of neoplastic cutaneous cells 2. The immunosuppression is exerted not only on cells in the skin but also those brought near the body surface in the cutaneous blood vessels. An important feature of the © 1985, Elsevier Science Publishers B.V., Amsterdam 0167 - 4919/851502.00

immunosuppression is failure of proliferation of cytotoxic T-cells. Two signals are required for such proliferation to occur: presentation by epidermal cells of antigen in conjunction with I-region products, and production of nonspecific amplifying factors such as interleukin 1 (IL-1)t The Langerhans cells (LC) of the skin are part of the system of dendritic cells. They have Ia markers and function as the antigen presenting cells of the skin. U V L decreases the number of LC or, by an unknown mechanism, interferes with their function and thus impairs their ability to stimulate antigen-specific T-cell proliferation. In addition to LC-induced IL-1 production, the keratinocytes produce an IL-1 like substance known as epidermal cell thymocyte activating factor (ETAF). After completion of antigen processing by LC the amount of ETAF produced appears, at least to some extent, to determine the magnitude of the ensuing T-cell proliferative response 8. Chronic U V L exposure not only impairs LC function but also reduces E T A F production and further hampers the stimulation of immune T-cells 9. While impaired ETAF/IL-1 production has been demonstrated under certain experimental conditions, in other studies production of this mediator was actually enhanced 1°. Differences in dosage of U V L and differences in the light sources used for irradiation may account for the discrepancies in measured levels of ETAF/IL-11° Why then is the immune response impaired in spite of high levels of E T A F / I L - 1? Gahring et al. lo suggest that there is decreased sensitivity of the target cell (helper T-lymphocyte) to stimulation by ETAF-IL- 1. This may be due to a down regulation of target cell surface receptor density, a depression of receptor affinity for ligand, or an increase in specific inhibitors of ETAF/IL- 1. The important rote of U V L in depressing LC function is borne out in experiments with other dendritic cells. In a mixed lymphocyte reaction U V radiation of dendritic cells completely abrogated their allostimulatory capacity 11. If rat islets of Langerhans (which contain dendritic cells) are treated in vitro with U V L and then transplanted allogeneically across a major histocompatibility barrier there is prolonged allograft survival even without the use of immunosuppressive agents 11.

Immunology Today, vol. 6, No, 7, 1985

Another major mechanism by which U V L induced tumors may escape immune destruction is by the generation of T suppressor cells. Experiments in mice showed that 80% of U V L induced tumors did not grow when transplanted into normal mice syngeneic with the animals in which the neoplasms arose (regressor tumors), but 20% did grow (progressor tumors) 12. While normal mice rejected transplants of most U V L induced tumors, those that first received a subcarcinogenic dose of U V L were no longer tumor resistant but permitted the progressive growth of transplanted U V L induced tumors. Further experiments using transfer of viable lymphoid cells, but not serum, from mice exposed to short term UVL, converted normal mice into tumor susceptible hosts. The above results are explained by the generation of suppressor T lymphocytes 12. It is not known how U V L induces these cells. Perhaps it immobilizes certain cell surface antigens, which when presented by LC provide tolerogenic signals to the immune system 12. U V L induced tumors are highly antigenic and possess tumor specific antigens 13. They have both unique and common antigens which stimulate specific immunity, and also, cross reactive immunity to many UVL-induced tumors. U V L may cause several types of suppressor response under varying experimental conditions 12. Suppressor cells with functional specificity for the unique tumor antigens control the re-expression of an antitumor response in tumor immune animals. Suppressor cells that are capable of controlling responses to the unique or to the common antigen act by inhibiting the generation of a primary response or the expression of a secondary response. If suppressor cells for common tumor antigens are already present then suppressor cells for the unique antigens are not generated. Several workers emphasize that suppressor cells play an important role in permitting U V L induced tumors to escape effective rejection reactions m3. There are other ways by which UV-B may impair immune responses in the skin 8. For example, UV-B may alter the Ia antigens in LC and contribute to their inability to initiate optimal T-cell responses. In addition, UV-B irradiated epidermal ceils may liberate prostaglandins that may suppress immune responses in the skin. Loss of antigen or masking of antigenic sites may also hamper the development of appropriate immune responses 6. Several factors may increase susceptibility to U V L carcinogenesis. These include genetic differences, chemicals, immunosuppressive agents, oncogenic viruses and exposure to heat, high humidity and wind 2'6'14. Experiments in different strains of hairless and other mice have shown huge differences in genetic susceptibility to photocarcinogenicity14. Humans with the genetic disorder xeroderma pigmentosum are particularly susceptible to the carcinogenic effects of sunlight 7. It is not known whether U V L contributes to melanoma development in patients with other genetic disorders, such as the familial dysplastic nevus syndrome or other types of familial melanoma. Animal experiments have shown that certain chemicals, particularly those that are photoactive or are themselves carcinogenic, increase the carcinogenicity of UVL. These include coal tar, eosin, hematoporphyrin, psoralens, croton oil, retinoic acid, B C N U and several

207 polycyclic hydrocarbon compounds 6'14. In man the combination of psoralens and UV-A (PUVA), used in the treatment of psoriasis and other skin diseases, may act as a cutaneous co-carcinogen in predisposed patients 15. Concern has also been expressed about the possible carcinogenic effect of 5-methoxypsoralen, the melanogenic component present in several suntan preparations 16. In animal experiments the combination of U V L with an immunosuppressive agent either azathiaprinC 7 or antilymphocyte serum 18, caused a higher yield of skin cancers than when either agent was used alone. Similarly immunosuppressed human organ transplant recipients have a high incidence of skin cancers, the rate varying with the amount of exposure to sunshine 19. With low ex o posure the incidence increases 4 to 7 fold, but with high exposure the incidence is increased 21 fold over the already high incidence in the local control population. Several immunologic changes may be pertinent to the development of these skin cancers. The glueocorticosteroids decrease the number and alter the morphology and function of LC and thus impair antigen presentation to T-cells 2°. In 9 immunosuppressed renal transplant recipients (two of whom had skin cancers) LC morphology and functions were abnormal when compared with controls. The disturbances were most marked in sunexposed areas of the skin 21. In another study 18 transplant patients who developed skin cancers had significantly greater depression of responsiveness of peripheral blood mononuclear cells to phytohemaglutinin, allogeneic lymphocytes and recall antigens than did 172 transplant recipients who did not develop cancers 2~. In contrast with these positive findings, a study of 32 kidney transplant recipients with skin cancer and another 32 recipients matched for age, sex, and duration of graft function, showed no significant differences in natural-cell mediated cytotoxicity23. Some workers have noted a parallel between carcinomas that appear on the faces, ears and vulvas of sheep and on the eyes of cattle, living in tropical and subtropical areas, with skin cancers in humans living in the same environment 24. Isolation of papillomaviruses from man and animals prompted the investigators to postulate that both actinic radiation and a papillomavirus contribute to the development of some of the lesions. This theory is strengthened by the observation that wart virus infections occur in at least 43 % of organ transplant recipients 19, that papillomavirus type 5 has been isolated from skin cancers in a transplant patient 25, and that squamous cell carcinomas may arise in viral warts 26. The association is strengthened by the fact that 35 % of patients with epidermodysplasia verruciformis develop squamous cell carcinomas in pre-existing viral warts, and the tumors usually arise in areas of sunexposed skin 27. As herpes simplex virus infections are very common in transplant recipients another possibility must be considered. As U V L may reactivate latent herpes viruses 2~it is possible that such viruses may act in combination with U V L to cause the high incidence of lip cancers seen in these patients19. ~[] ISRAEL PENN Department of Surgery, University of Cincinnati Medical Centre, Cincinnati, Ohio 45267, USA.

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References 1 Silverberg, E. (1985) Cancer35, 19-35 2 Penn, I. (1984) Immunol. Today 5, 291-293 3 Binm, H. F. (1959) in Garcinogenesis by Ultraviolet Light: An Essay in Quantitative Biology, PrincetOn University Press, Princeton 4 Chan, J. T. and Black, H. S. (1974)Science 186, 1216-1217 5 O'Brien, T. G. (1976) CancerRes. 36, 2644-2653 6 Epstein, J. H. (1978) Natl CancerInst. Monogr. 50, 13-25 7 Gleaver, J. E. (1969) Proc. NatlAcad. Sci. USA 63, 428 8 Stingl~L. A., Sauder, D. N., Iljima, M., Wolff, K., Pehamburger, H. and Stingl, G. (1983).f Immunol. 130, 1586-1591 9 Sander, D. N., Noonan, F. P., Defabo, E. C. and Katz, S. I. (1983)J. Invest. Dermatol. 80, 485-489 10 Gahring, L., Balm, M., Pepys, M. B. and Daynes, R. (1984)Proc. Natl Acad. Sci. USA 81, 1198-1202 11 Lau, H., Reemtsma, K. and Hardy, M. AI (1984) Science223, 607-609 12 Spellman, G. W. and Daynes, R. A. (1981) Hum. Pathol. 12, 489-491 13 Krlpke, M. L. (1984) Tran.~plant. Proc. 16, 474-475 14 Urbach, F., Forbes, D. P. and Davies, R. E. (1982).]'. Natl Cancer. Inst. 69, 229-235

15 Roelandts, R. (1984)Arch. Dermatol. 120, 662-669 16 Faldela , F. and Bisagni, E. (1981) Garcinogencsis2, 121-127 17 Koranda, F. G., Loeffler, R. T., Koranda, D. M. and Penn, I. (1975) 8urg. Forum 26, 145-146 18 Nathanson, R. B., Forbes, P. D. and Urbaeh, F. (1973) Proc. Am. Assoc. Cancer Res. 14, 46 19 Penn, I. (1980) Glin. Plast. Surg. 7, 361-368 20 Belsito, D. V., Flotte, T.J., Lira, H. W., Baer, R. L., Thorbecke, G. J. and Gigli, I. (1982)J. Exp. Med. 155, 291-302 21 Sontheimer, R. D., Bergstresser, P. R., Gailiunas, P. (Jr.), Helderman, J. H. and Gilllam, J. N. (1984) Transplantation 37, 168-174 22 Kelly, G. E., Shell, A. G. R. and Taylor, R. (1984) Transplantation 37, 368--372 23 Rigby, R. J., Gollogly, R. K., Robinson, M. F., Hardie, I. R. and Petrie, J. J. B. (1984) Transplantation 37, 526-529 24 Spadbrow, P. B., Beardmore, G. L. and Francis, I. (1983) Lancet i, 189 25 Luntzner, M. A., Orth, G., Dutronquay, V., Ducasse, M. F., Kreis, H. and Crosnier, J. (1983) Lancet ii, 422-424 26 Phillips, M. E. andAckerman, A. B. (1982)Am.J. Dermatopath. 4, 61--84 27 Luntzner, M. A. (1978) Bull. Cancer65, 169-182 28 Lytle, C. D. (1978) Natl CancerInst. Monogr. 50, 145-149

Myc/Igjuxtaposition by chromosomal translocations: some new insights, puzzles and paradoxes George Klein and Eva Klein Human Burkitt's lymphoma and murine plasmacytoma cells contain characteristic chromosomal translocations 1 that show thefollowing common features.'juxtaposition of the c-m y c oncogene to one of the three immunoglobulin locie-4," wide variability of the transIocation breakpoint in and outside the oncogene, but with rigorous avoidance of any damage to the two coding exons541," high expression of the Ig-juxtaposed c-myc gene with concomitant shutdown of the normal, nontranslocated allele ~,z,u,14,~5,18. The latter•act suggests that the transl•cati•n has rem•ved the •nc•gene fr•m its n•rmal regulatory circuit and placed it under the constitutively activating influence of an Ig-locus. This is believed to play an essential role in the malignant transformation 2~. Numerous papers have dealt with the possible role of the translocations in tumorigenesis. Less attention has been given to their implications with regard to the normal D N A rearrangement process that takes place during B-cell differentiation. In this article, George and Eva Klein consider both areas and their interrelations.

It is reasonable to assume that tile translocations occur during the normal rearrangement of the Ig-genes which create vulnerable sites and increase the risk of illegitimate recombination. In the typical, i.e. most common, translocations, the transposed myc-gene joins one of the I g H switch sites, suggesting that the switch recombination enzymes participate in the event. Exceptions where the I g H cluster breaks elsewhere, e.g. in the neighborhood of a J sequence or within the V H region, do occur, but are rare 2.a5. The less frequent variant translocations 19'z° involve one of the light chain loci. The switch regions can therefore be regarded as favored hot spots, but they are not exclusive translocation sites. There are no similar hot spots within or in the vicinity of the c-myc gene: the variability of the breakpoints is much too great. In the majority of the 12 ; 15 translocations in murine plasmacytomas (MPCs) and in a substantial fraction of the 8 ; 14 translocations in Burkitt's lymphomas (BLs), the break occurs within exon 1 or intron 1 of the gene, however. The break can also occur outside the gene; this happens more frequently in BL than in M P C .

In the typical (IgH) translocations the breaks are always upstreams of the gene in both species. T h e y can be located between the 5'-end of c-myc and the nearest EcoR I restriction site (1 0 kb in the mouse, 17 kb in man) or further upstreams, outside the restriction site. The m a x i m u m distance that is compatible with the t u m o r phenotype is not known, but it is likely that the cis-activating effect of the IgH locus can act on the myc-gene over considerable distances i~. The variant translocations that involve one of the light chain loci 26a7 differ from the I g H translocations in two ways, at least in the more extensively investigated BL system. The first difference is that chromosome 8 breaks downstreams of the c-myc gene and the C~ppa or Cj,,nbd~ sequences are transposed to it telomericaUy, carried by the terminal fragments of chromosome 2 or chromosome 2218-2°. The second important difference concerns the relative orientation ofc-myc and the juxtaposed Ig-region. The IgH sequences face c-myc head to head in the typical translocations. In the variant translocations the 5'-end of the transposed light chain sequences face the tail end of

c-myc. Department of Tumor Biology, Karolinska Institute, ~Box60 400, S-104 01 Stoekhohn, Sweden. (~ 1985,ElsevierSciencePublishersB.V.,Amsterdam 0167- 4:919/85/|02.00

These differences m a y be trivial and merely reflect the orientation of the participating genes or m a y have some

New directions in research Ultraviolet light and skin cancer.

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