Open AccessHIF1-positive and HIF1-negative glioblastoma cells compete in vitro but cooperate in tumor growth in vivo
Author(s) -
Paolo Fiorenzo,
Maria Patrizia Mongiardi,
Diletta Dimitri,
Mauro Cozzolino,
Alberto Ferri,
Nicola Montano,
Gianluca Trevisi,
Giulio Maira,
Luca Battistini,
Maria Laura Falchetti,
Andrea Levi,
Roberto Pallini
Publication year - 2010
Publication title -
international journal of oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.405
H-Index - 122
ISSN - 1019-6439
DOI - 10.3892/ijo_00000554
Subject(s) - in vivo , oncogene , biology , glioblastoma , in vitro , cell cycle , molecular medicine , cancer research , tumor cells , apoptosis , microbiology and biotechnology , genetics
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.