TY - JOUR
T1 - Angiogenesis-independent tumor growth mediated by stem-like cancer cells
AU - Sakariassen, Per
AU - Prestegarden, Lars
AU - Wang, Jian
AU - Skaftnesmo, Kai Ove
AU - Mahesparan, Rupavathana
AU - Molthoff, Carla
AU - Sminia, Peter
AU - Sundlisæter, Eirik
AU - Misra, Anjan
AU - Tysnes, Berit Bølge
AU - Chekenya, Martha
AU - Peters, Hans
AU - Lende, Gabriel
AU - Kalland, Karl Henning
AU - Øyan, Anne M.
AU - Petersen, Kjell
AU - Jonassen, Inge
AU - Van Der Kogel, Albert
AU - Feuerstein, Burt G.
AU - Terzis, A. Jorge A.
AU - Bjerkvig, Rolf
AU - Enger, Per Øyvind
PY - 2006/10/31
Y1 - 2006/10/31
N2 - 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.
AB - 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.
KW - Glioma
KW - Invasiveness
KW - Vessel cooption
UR - http://www.scopus.com/inward/record.url?scp=33750814849&partnerID=8YFLogxK
U2 - 10.1073/pnas.0607668103
DO - 10.1073/pnas.0607668103
M3 - Article
C2 - 17056721
AN - SCOPUS:33750814849
SN - 0027-8424
VL - 103
SP - 16466
EP - 16471
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 44
ER -