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Carcinogenesis, Vol. 20, No. 8, 1521-1528, August 1999
© 1999 Oxford University Press

Carcinogenesis

An in vitro model of the early genetic events in multistage carcinogenesis of malignant insulinoma

Masa Katic, Mirko Hadzija, Mercedes Wrischer1 and Kresimir Pavelic2

Division of Molecular Medicine and
1 Division of Molecular Genetics, Rudjer Boskovic Institute, Bijenicka 54, 10 000 Zagreb, Croatia

The aim of this study was to establish an in vitro model to confirm earlier observations on the role of the myc/ras oncogenes as promoting factors in the process of normal Langerhans islet ß cell transformation. For that purpose we infected primary mouse Langerhans islets with a recombinant retrovirus containing the v-H-ras and v-myc oncogenes, before or after treatment with transforming growth factor {alpha} (TGF{alpha}). Normal Langerhans islets, when grown in culture, are viable for 2–3 weeks. After treatment with TGF{alpha}, viability was extended by 10 days, following which islets disintegrated. Langerhans islets transformed with v-H-ras and v-myc became immortal and insulin negative. Single infected ß cells, liberated from a primary islet into the surrounding medium, gave rise to neo islet formation. Moreover, single infected ß cells were able to grow and divide, even without fibroblast support. These results indicate that the myc and ras oncogenes are sufficient for commencement of ß cell transformation and, therefore, could represent `early events' in the multistep carcinogenesis of insulinomas.

Abbreviations: c.f.u., colony forming units; EGF-R, epidermal growth factor receptor; FCS, fetal calf serum; HeBS, HEPES-buffered saline pH 7.05; PBS, phosphate-buffered saline; TGF{alpha}, transforming growth factor {alpha}

2 To whom correspondence should be addressed Email: pavelic{at}rudjer.irb.hr


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