Angiogenesis-independent tumor growth mediated by stem-like cancer cells.
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.
Sakariassen
Per Ø
PØ
NorLux NeuroOncology, Department of Biomedicine, University of Bergen, N-5020 Bergen, Norway.
Prestegarden
Lars
L
Wang
Jian
J
Skaftnesmo
Kai-Ove
KO
Mahesparan
Rupavathana
R
Molthoff
Carla
C
Sminia
Peter
P
Sundlisaeter
Eirik
E
Misra
Anjan
A
Tysnes
Berit Bølge
BB
Chekenya
Martha
M
Peters
Hans
H
Lende
Gabriel
G
Kalland
Karl Henning
KH
Øyan
Anne M
AM
Petersen
Kjell
K
Jonassen
Inge
I
van der Kogel
Albert
A
Feuerstein
Burt G
BG
Terzis
A Jorge A
AJ
Bjerkvig
Rolf
R
Enger
Per Øyvind
PØ
D000818:Animals; D001706:Biopsy; D002877:Chromosomes, Human / Q000235:genetics; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D051381:Rats; D011923:Rats, Nude; D015398:Signal Transduction; D013234:Stem Cells; D015996:Survival Rate; D014407:Tumor Cells, Cultured