PMID- 15899805
OWN - NLM
STAT- MEDLINE
DCOM- 20050707
LR  - 20220318
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 10
DP  - 2005 May 15
TI  - The role of hypoxia-inducible factor-1 in three-dimensional tumor growth, 
      apoptosis, and regulation by the insulin-signaling pathway.
PG  - 4147-52
AB  - The purpose of this study was to establish the effect of hypoxia-inducible 
      factor-1 (HIF-1) directly on tumor growth, independently of angiogenesis. This 
      was done by growing wild-type mouse hepatoma cells (HEPA-1) and their 
      HIF-1-deficient counterpart C4 as multicellular tumor spheroids and quantifying 
      differences in growth rates and proliferative and apoptotic indices. Insulin and 
      insulin-like growth factor-I are key growth factors, also able to regulate 
      hypoxia-responsive genes via HIF-1; thus, the effects of insulin on this model 
      were also investigated. Two-dimensional growth was serum dependent and no 
      difference was seen between wild-type HEPA-1 and C4 cell growth profiles, but 
      major differences were seen in three-dimensional growth. HIF-1 supported spheroid 
      growth under hypoxia as the HEPA-1 spheroids grew faster than the C4. 
      Surprisingly, the HIF-1-deficient cells had a higher proliferation rate in 
      three-dimensional growth (C4 mean S-phase index, 13.6%; HEPA-1 mean S-phase 
      index, 9%; P = 0.009) that was associated with an inhibition of apoptosis. 
      However, the apoptosis rate was much greater in these spheroids (C4 mean 
      apoptotic index, 6.4; HEPA-1 mean apoptotic index, 0.78%; P = 0.0006). Addition 
      of insulin increased proliferation and apoptosis in both HEPA-1 and C4 spheroids, 
      demonstrating an HIF-1-independent effect of insulin signaling in 
      three-dimensional growth. These results indicate that the enhancing effect of 
      HIF-1 in three-dimensional tumor growth is a balance of both reduced 
      proliferation and enhanced survival, the latter being proportionally greater.
FAU - Leek, Russell D
AU  - Leek RD
AD  - Growth Factor Group, Cancer Research UK Molecular Oncology Laboratories, 
      Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University 
      of Oxford, Oxford, United Kingdom.
FAU - Stratford, Ian
AU  - Stratford I
FAU - Harris, Adrian L
AU  - Harris AL
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Chromones)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Insulin)
RN  - 0 (Morpholines)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Transcription Factors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects/*physiology
MH  - Cell Growth Processes/physiology
MH  - Cell Line, Tumor
MH  - Chromones/pharmacology
MH  - DNA-Binding Proteins/drug effects/*physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Insulin/*pharmacology
MH  - Liver Neoplasms, Experimental/*pathology
MH  - Mice
MH  - Morpholines/pharmacology
MH  - Nuclear Proteins/drug effects/*physiology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - S Phase/physiology
MH  - Signal Transduction/drug effects/physiology
MH  - Spheroids, Cellular
MH  - Transcription Factors/drug effects/*physiology
EDAT- 2005/05/19 09:00
MHDA- 2005/07/08 09:00
CRDT- 2005/05/19 09:00
PHST- 2005/05/19 09:00 [pubmed]
PHST- 2005/07/08 09:00 [medline]
PHST- 2005/05/19 09:00 [entrez]
AID - 65/10/4147 [pii]
AID - 10.1158/0008-5472.CAN-04-2184 [doi]
PST - ppublish
SO  - Cancer Res. 2005 May 15;65(10):4147-52. doi: 10.1158/0008-5472.CAN-04-2184.