Pigment Cell Research in Australasia

Peters Parsons,. Queensland Institute of Medical Research
Herston, Brisbane, Australia 4006

The aim of this review is to briefly outline current research areas. A few key references have been included for further information. Detailed accounts of the epidemiology and treatment of melanoma in Australia and New Zealand have recently been published (Trans. Menzies Foundation, vol. 15: 1990; Cancer Forum, 14:1-34, 1990; Med. J. Aust. 150: 469-470, 1989).

Pigment cell research in Australia is centred largely on the biology and treatment of human melanoma, due to the 1 in 50 lifetime risk of this tumour. Thus the state of Queensland, one of the few subtropical areas in the world sustaining a large Caucasian population, has the highest incidence globally (40 per 10⁵ per annum) and apparently doubling each decade. Since Lancaster's original suggestion of a solar aetiology (Med. J. Aust., 1:452, 1957) there have been many epidemiological studies of melanoma in Australia. notably Armstrong's group in Perth documenting the risk associated with exposure in childhood (JNCI. 72:257-266, 1984) and Green and others in Brisbane describing moles and sunburn as major risk factors in adults and children (Epidemiol. Rev., 11:204-221, 1989; J. Am. Acad Dermatol 20:1054-1060, 1989). Following on from earlier work (Ann. Human Biol., 8:529-541, 1981), Martin and co-workers in Brisbane are studying naevus patterns and skin relectance in twins with and without melanoma. McLennan et al. are looking at the dependence of naevi formation on latitude and other factors. Across the Tasman Sea in the scenic South Island of New Zealand, Elwood and his colleagues at the University of Otago in Dunedin are involved in the epidemiology of naevi and melanoma (Int. J. Cancer, 36:175-178, 1985; N.Z. Med. J., 101:602-604, 1988). There is a perceived need to compare the epidemiology and biology of nonmelanoma skin cancers (associated with chronic solar exposure) with that of melanoma (associated with acute exposure) so that a biological basis for the latter can be established, and there is concern about the ozone layer particularly the Antarctic ozone hole. The incident UV flux and exposure times in Australia are probably much higher than in the northern hemisphere and consequently may give different patterns of skin carcinogenesis.

Despite the large population of cattle and sheep in Australia melanoma appears to be rare in these animals. Recently a significant number of melanomas has been found in goats, enabling a melanoma cell line to be established (Parsons et al, in press). Reeve and Greenoak in Sydney use hairless, pigmented mice for a variety of studies including evaluation of sunscreens and antioxidants (Photochem. Photobiol. 48:689-696, 1988).

Despite the high risk of melanoma, the death rate (about 4 per 10⁵ per annum) remains relatively low, presumably reflecting the success of early and effective surgery in a population alerted to the problem. Supported by government funds and state cancer societies, imaginative education programmes aimed particularly at young people urge protection from solar UV by all possible means and early removal of suspicious lesions. A television documentary featuring a young man with melanoma directly resulted in approximately 750 new cases of melanoma being diagnosed in the following 6 months (McCarthy and Shaw, Cancer Forum 14:6-10, 1990).

Financed mainly by the state cancer societies and the federal National Health & Medical Research Council, research on melanoma in Australia owes much to the logistic support of the clinicians who established and maintain centres for treatment and research. These groups include the Sydney Melanoma Unit, which is the largest melanoma treatment centre in the world, and the Queensland Melanoma Project in Brisbane. In addition to making important contributions to the diagnosis and treatment of melanoma, these centres identify and monitor melanoma-prone families andcollaborate in linkage studies of familial melanoma/dysplastic naevus syndrome (Kefford et all Cancer Genet. Cytogenet, in press) and mapping melanoma-associated genes or chromosomal regions (Dracopoli et al, PNAS, 86: 4614-4618, 1989;Hayward et al, Int J. Cancer, 42:558-561, Human Genet. 83: 395-396, 1989). Unlike certain families in the United States, Australian melanoma families have so far shown no evidence ol linkage to chromosome 1p. Such differences may be part of the heterogeneity and genetic instability which bedevils attempts to understand and control melanoma.

The establishment of human melanoma cell lines by Whitehead and Little at the Queensland Institute of Medical Research in Brisbane (Pigm. Cell 1:383-389, 1973)marked the beginning of a wide range of experimental studies of which only some current aspects can be mentioned here. Evidence that TGFÑ is a mediator of the UV response in melanocytic cells (Ellem et al, Carcinogenesis, 9:797-801, 1988) has been confirmed in studies of sun-irradiated humans; regulation of TGFÑ activity is now being examined. Direct sunlight is being used as an experimental light source to induce mutation in melanocytic cells where aberrant nucleoside metabolism may play a role in enhancing mutagenesis (Musk et al, Mutat. Res. 227:25-30, 1989). Other peculiarities of cultured melanoma cells under study include deficiency in DNA methylation repair (Maynard et al, Cancer Res., 46:5009-5013, 1989) and sensitivity to buthionine sulphoximine (Kable et al, Cancer Res., 49:2327-2331, 1989). This work overlaps with analysis of pigmentation control, key tools being in-house monoclonal antibodies, affinity purification and N-terminal sequencing of active sulphydryl proteins, glycosylation inhibitors, novel marine compounds, UV-induced factors, and immunohistochemistry of clinical material (Takahashi et al., Virchows Archiv. A, 416:513-519, 1990). In Sydney, natural modulators of melanogenesis including Vitamin D are under study in melannma cells (Mason et al, J. Invest. Dermatol., 90:334-340,1988) and melanocytes (idem. 90:593-598, 1988).

Non-surgical therapy of melanoma is being investigated in several centres. McLeod and Thomson in the Queensland Melanoma project are involved in clinical trials of interferon and DTIC (Br J. Clin. Pract. Symp. Suppl., 62:22-26, 1988) as well as video imaging of dysplastic naevi, quality of life studies and maintenance of an extensive data bank. The Sydney Melanoma Unit has used a variety of agents (Coates et al, Pigm. Cell Res., 2: 370-371, 1989), including neutron capture therapy in collaboration with Alien and his colleagues (Brown et al, Pigm. Cell Res., 2: 319-324, 1989). The Melanoma Unit in Newcastle has a particular interest in immunotherapy, currently involving clinical trials of immunization with vaccinia melanoma cell lysates (Hersey et al., Cancer Immunol. Immunotherapy 25:257-265, 1987). In vitro analysis of melanoma antigens is based on detection by antibodies using Western blot techniques (Int. J. Cancer, 46: 612-617, 1990) and T cell responses using nitrocellulose immobilized antigen (J. Natl. Canc. Inst. 80:826, 1988). Studies in Newcastle also include assessment of the effects of UV on the human immune system, in particular the dose dependent inhibition of NK activity by UV-A.

Although these groups are geographically distant, researchers meet regularly at national conferences, for example the Clinical Oncology Society of Australia conference in November, as well as at melanoma meetings held from time to time on special topics. Whether for a conference, sabbatical, postgraduate degree or fellowship period, travel to Australia offers a variety of opportunities for pigment cell researchers as well as interesting natural environments and the double-edged attraction of a sunny climate. Australian researchers actively collaborate with overseas groups and welcome enquiries from prospective visitors, who are encouraged to make contact at an early stage so that suitable arrangements can be made.