[Molecular techniques lead to the first insights into the pathophysiology of salivary gland adenomas]

Pleomorphic adenomas are the most common type of salivary gland tumours. Activation of the PLAG1 gene on chromosome 8q12 is the most frequent mutation found in these tumours. This results from chromosomal translocations leading to promoter substitution between PLAG1, mainly expressed in fetal tissue, and more broadly expressed genes. The replacement of the PLAG1 promoter, inactive in adult salivary glands, by a strong promoter derived from the translocation partner, leads to ectopic expression of PLAG1 in the tumor cells. This abnormal PLAG1 expression results in deregulation of PLAG1 target genes causing salivary gland tumorigenesis. PLAG1 binds to promoter 3 of the Insulin-like growth factor 2 gene (IGF2) and stimulates its activity. IGF2 is highly expressed in salivary gland adenomas overexpressing PLAG1 while no IGF2 expression is found in adenoma without abnormal PLAG1 expression nor in normal salivary gland tissue, indicating a perfect correlation between PLAG1 and IGF2 expression. These results provide us with the first clue for understanding the role of PLAG1 in salivary gland tumor development. IGF2 perfectly fits in the picture of a restarted developmental program with concomitant loss of differentiation, the typical hallmark for any tumour. Salivary gland genesis provides a system for studying the development of glandular organs having many basic features in common with the salivary gland, such as breast, kidney, lung, pancreas and prostate. With a unique salivary gland organ culture system we now can study principles of epitheliogenesis, tubulogenesis and branching morphogenesis. Genes expressed at the spot where during tumourigenesis proliferation overrules differentiation constitute new targets for reverting the proliferative, tumour-specific stage. By elucidating molecular mechanisms involved in human cancer, we will hence contribute at the level of fundamental cancer research (oncogenesis) and normal organ development (organogenesis).