Carcinogenesis, Vol 19, 673-681, Copyright © 1998 by Oxford University Press
JS Rhim, WP Tsai, ZQ Chen, Z Chen, C Van Waes, AM Burger and JA Lautenberger
Endothelial cell biology has recently been the subject of considerable
interest in thrombosis and cancer research. However, the successful
establishment of immortalized human endothelial cells which retain
differentiated cell characteristics has been rare. We have successfully
established immortalized human umbilical vein endothelial cells (HUVECs) by
human papilloma virus (HPV)-16 E6-E7. HPV-16 E6, E7 and E6- E7 were
successfully introduced into HUVEC cells. Both E6 and E7 cultures had an
extended lifespan but eventually underwent senescence. E6-E7 cultures
4-5-2G, however, acquired an indefinite lifespan in culture but did not
undergo malignant conversion. Telomerase activity was not detected in
either E6 or E7 cultures; however, telomerase was detected in E6-E7 4-5-2G
cells. The cells exhibited a 'cobblestone' morphology and developed a
capillary-like tube structure upon reaching confluence. The 4-5-2G line
expressed Factor VIII related antigen and took up DiI-Ac-LDL as markers of
endothelial origin. The line expressed integrin subunits (alpha(v)beta3,
alph(v)beta5, beta1, alpha2, alpha3, beta4 and alpha6) consistent with an
endothelial origin. The higher passage of 4-5-2G line showed a similar
intensity of integrin immunostaining to that of primary HUVECS. Subsequent
infection of these immortal cells with the Kirsten murine sarcoma virus
which contains an activated K-ras oncogene induced morphological
transformation that led to the acquisition of invasion capability and
neoplastic properties. Telomerase was also detected in the tumorigenic
v-Ki-ras transformed cell line. These cell lines should be useful for
studies of the molecular mechanisms underlying normal and neoplastic
endothelial cell proliferation and migration, and might also provide an in
vitro model for development of pharmacologic and gene therapy for
cardiovascular thrombosis and cancer.
ARTICLES
A human vascular endothelial cell model to study angiogenesis and tumorigenesis
Laboratory of Biochemical Physiology, National Cancer Institute, Frederick, MD 21702, USA. rhimi@fcrfv1.ncifcrf.gov
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