Methylnitrosourea-induced carcinoma in organ-cultured fetal human pancreas

Explants from 12- to 14-week-old human fetal pancreases were organ cultured in a chemically defined medium and cultured for up to 12 months in the presence or absence of methylnitrosourea (MNU). Differentiation of the exocrine pancreas occurred in vitro, and explants cultured in the absence of MNU for 4 weeks or longer revealed normal acinar structures with zymogen granules. Ducts and ductules also developed normally. The undifferentiated tubular structures of the 12- to 14-week fetal pancreas expressed neither ductal nor acinar cell markers. Acinar cell surface marker appeared first after 2 weeks of culture, and the development of centroacinar and ductal cell markers followed 2 to 4 weeks later. MNU-treated explants showed minimal degeneration and necrosis. MNU caused early loss of apical cytoplasm and zymogen granules in acinar cells, resulting in dilation of acinar lumens, concomitant proliferation of cells bearing duct cell markers, and ductal hyperplasia. Enhanced foci of proliferation and carcinoma developed within 3 and 5 months of treatment, respectively. Cells derived from 4- to 5-month MNU-treated explants were tumorigenic in nude mice. Tumor cells revealed a human karyotype and expressed duct cell surface markers.