Am. Burger et al., EFFECT OF ONCOGENE EXPRESSION ON TELOMERASE ACTIVATION AND TELOMERE LENGTH IN HUMAN ENDOTHELIAL, FIBROBLAST AND PROSTATE EPITHELIAL-CELLS, International journal of oncology, 13(5), 1998, pp. 1043-1048
Although strong evidence is mounting that telomerase reactivation and
the thereof resulting stabilization of telomeres is a major mechanism
for human cells to overcome replicative senescence, a causal relations
hip linking telomerase activation conclusively to tumorigenesis remain
s to be established. Thus, the possibility exists that telomerase acti
vation is passively co-selected as tumors develop. To elucidate the fu
nction of telomerase during tumorigenesis, we followed telomerase reac
tivation during immortalization of human primary cell types with in vi
tro transforming agents and determined the tumorigenic potential of th
ese cells at various stages of transformation. The effects of SV40, v-
Ki-ms, HPV-18 and HPV-16 E6/E7 oncoproteins on telomerase expression w
as examined in primary and immortalized human prostate epithelial (HPE
), human prostate fibroblast (HPF), and umbilical vein endothelial cel
ls (HUVEC). All of five SV40-transformed HPE and HPF lines were telome
rase positive and had shorter telomeres than primary cells. The two HP
V-18 immortalized HPE cell lines also expressed telomerase activity. I
n contrast, EG or E7 alone could not produce immortalized HUVEC and di
d not reactivate telomerase. Life-span, however, was extended. The E6/
E7 immortalized HUVEC had telomerase activity and short but stable tel
omeres. HPE, HPF or HUVEC cells which had been transformed by one onco
protein alone were not tumorigenic although they had overcome cellular
senescence and reactivated telomerase. However, if these cells were t
ransformed by a second agent, either infection with v-Ki-ras or X-ray
treatment, they were able to form tumors in nude mice. This suggests t
hat tumorigenesis is a multistep process and that telomerase activatio
n alone is not sufficient for malignant transformation in human cells.