Angiogenesis-independent tumor growth mediated by stem-like cancer cells

Per Ø Sakariassen, Lars Prestegarden, Jian Wang, Kai-Ove Skaftnesmo, Rupavathana Mahesparan, Carla Molthoff, Peter Sminia, Eirik Sundlisaeter, Anjan Misra, Berit Bølge Tysnes, Martha Chekenya, Hans Peters, Gabriel Lende, Karl Henning Kalland, Anne M Øyan, Kjell Petersen, Inge Jonassen, Albert van der Kogel, Burt G Feuerstein, A Jorge A TerzisRolf Bjerkvig, Per Øyvind Enger

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors.

Original languageEnglish
Pages (from-to)16466-71
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number44
DOIs
Publication statusPublished - 31 Oct 2006

Cite this

Sakariassen, P. Ø., Prestegarden, L., Wang, J., Skaftnesmo, K-O., Mahesparan, R., Molthoff, C., Sminia, P., Sundlisaeter, E., Misra, A., Tysnes, B. B., Chekenya, M., Peters, H., Lende, G., Kalland, K. H., Øyan, A. M., Petersen, K., Jonassen, I., van der Kogel, A., Feuerstein, B. G., ... Enger, P. Ø. (2006). Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 103(44), 16466-71. https://doi.org/10.1073/pnas.0607668103