VON-HIPPEL-LINDAU GENE-MEDIATED GROWTH SUPPRESSION AND INDUCTION OF DIFFERENTIATION IN RENAL-CELL CARCINOMA-CELLS GROWN AS MULTICELLULAR TUMOR SPHEROIDS

Citation
B. Lieubeauteillet et al., VON-HIPPEL-LINDAU GENE-MEDIATED GROWTH SUPPRESSION AND INDUCTION OF DIFFERENTIATION IN RENAL-CELL CARCINOMA-CELLS GROWN AS MULTICELLULAR TUMOR SPHEROIDS, Cancer research, 58(21), 1998, pp. 4957-4962
Citations number
29
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
58
Issue
21
Year of publication
1998
Pages
4957 - 4962
Database
ISI
SICI code
0008-5472(1998)58:21<4957:VGGSAI>2.0.ZU;2-T
Abstract
Previous results using gene transfection methods have shown that the w ild-type (WT) von Hippel-Liudau (VHL) gene can function as a potent tu mor suppressor gene in vivo for renal cell carcinoma (RCC) cells in th e absence of any suppressive effect on cell growth in monolayer cell c ulture under serum-rich conditions. Because we had previously found th at the function of some oncogenes, such as mutant ras, can be influenc ed by three-dimensional growth as multicellular spheroids (J, Rak et a l., J, Cell Biol,, 131: 1587-1598, 1995), we reasoned the same might b e true for suppressor genes as well. We, therefore, decided to compare and study the effects of the WT VHL gene in monolayer versus three-di mensional culture systems of the RCC cell line 786-0, which contains a n inactivated VHL gene. We found that the reintroduction of the WT VHL gene into mutant VHL RCC cells resulted in growth suppression in vitr o, but only when the cells were grown as spheroid cultures. This decre ase in cell proliferation was associated with several features of cell differentiation/morphogenesis, as shown by light and electron microsc opy. Thus, in contrast to cultures of mutant VHL RCC cells, which form ed very compact and cohesive spheroids, the WT VHL transfectants were loosely arranged and formed a network of tubular and trabecular struct ures within the spheroids. The morphological changes of the WT VHL sph eroids were associated with the,deposition of fibronectin in the extra cellular space, a feature that was absent in the mutant and inactivate d VHL gene-expressing spheroids. The results suggest the VHL gene may be involved in the maintenance of the epithelial phenotype of renal tu bular cells, i.e., it may act as a differentiation/morphogenetic facto r. Moreover, this effect in tumors cells appears to be highly dependen t on multicellular growth conditions that mimic the basic nature of so lid tumors, such as RCC.