Spontaneous Reversion of the Angiogenic Phenotype to a Non-angiogenic and Dormant State in Human Tumors

• Published in: Molecular cancer research Vol. 12; no. 5; pp. 754 - 764
• Main Authors: Rogers, Michael S., Novak, Katherine, Zurakowski, David, Cryan, Lorna, Blois, Anna, Lifshits, Eugene, Bø, Trond H., Oyan, Anne M., Bender, Elise R., Lampa, Michael, Kang, Soo-Young, Naxerova, Kamila, Kalland, Karl-Henning, Straume, Oddbjorn, Akslen, Lars A., Watnick, Randolph S., Folkman, Judah, Naumov, George N.
• Format: Journal Article
• Language: English
• Published: 26-02-2014
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-13-0532-T

The angiogenic switch, a rate-limiting step in tumor progression, has
already occurred by the time most human tumors are detectable. However, despite
significant study of the mechanisms controlling this switch, the kinetics and
reversibility of the process have not been explored. The stability of the
angiogenic phenotype was examined using an established human liposarcoma
xenograft model. Non-angiogenic cells inoculated into immunocompromised mice
formed microscopic tumors that remained dormant for ~125 days (vs. <40 days
for angiogenic cells) whereupon the vast majority (>95%) initiated
angiogenic growth with second-order kinetics. These original, clonally-derived
angiogenic tumor cells were passaged through four
in vivo
cycles. At each cycle, a new set of single-cell clones was established from the
most angiogenic clone and characterized for
in vivo
for
tumorigenic activity. A total of 132 single-cell clones were tested in the 2nd,
3rd and 4th
in vivo
passage. Strikingly, at each passage, a
portion of the single-cell clones formed microscopic, dormant tumors. Following
dormancy, like the original cell line, these revertant tumors spontaneously
switched to the angiogenic phenotype. Finally, revertant clones were
transcriptionally profiles and their angiogenic output determined. Collectively,
these data demonstrate that the angiogenic phenotype in tumors is malleable and
can spontaneously revert to the non-angiogenic phenotype in a population of
human tumor cells.