HIF1-positive and HIF1-negative glioblastoma cells compete in vitro but cooperate in tumor growth in vivo.
Glioblastoma multiforme (GBM) is characterized by extensive angiogenesis that is mostly orchestrated by the hypoxia inducible factor HIF-1. Deregulation of HIF-1 is believed to contribute to cancer initiation and progression. However, instances have been described in which loss of HIF-1 leads to more aggressive tumors. Here we investigated the consequences of downregulating HIF-1 function in the human GBM cell line TB10, both on cell proliferation in vitro and on tumor growth in vivo. RNA interference targeting the O2-regulated HIF-1alpha subunit efficiently reduced HIF-1alpha expression and transcriptional induction of HIF-1-responsive genes without affecting cell growth. Thus, singularly grown wild-type and HIF-1alpha-inhibited GBM cell populations did not significantly differ in proliferation rate. However, when the two populations were co-cultured, wild-type cells overgrew the HIF-1alpha-inhibited cells. Subcutaneous grafting in nude mice of wild-type and HIF-1alpha-inhibited GBM cells lead to comparable tumor formation and growth. Interestingly, cografting of wt and HIF-1alpha- inhibited GBM cells in nude mice resulted in more aggressive tumors, both in terms of tumor appearance and tumor growth. This suggests that cellular populations that differ in their ability to mount a response to hypoxia may compete in vitro but cooperate in vivo resulting in increased tumor aggressiveness.
Fiorenzo
Paolo
P
INMM-CNR, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
Mongiardi
Maria Patrizia
MP
Dimitri
Diletta
D
Cozzolino
Mauro
M
Ferri
Alberto
A
Montano
Nicola
N
Trevisi
Gianluca
G
Maira
Giulio
G
Battistini
Luca
L
Falchetti
Maria Laura
ML
Levi
Andrea
A
Pallini
Roberto
R
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D034622:RNA Interference; D013997:Time Factors; D014161:Transduction, Genetic; D047368:Tumor Burden
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit