PMID- 18339868
OWN - NLM
STAT- MEDLINE
DCOM- 20080409
LR  - 20121115
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 6
DP  - 2008 Mar 15
TI  - Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to 
      vascular endothelial growth factor inhibition.
PG  - 1872-80
LID - 10.1158/0008-5472.CAN-07-1589 [doi]
AB  - Antiangiogenic therapy improves survival in patients with advanced stage cancers. 
      Currently, there are no reliable predictors or markers for tumor vessel response 
      to antiangiogenic therapy. To model effective antiangiogenic therapy, we 
      disrupted the VEGF gene in three representative cancer cell lines. HCT116 
      xenografts had low proportions of endothelial tubes covered by pericytes that 
      stained with alpha-smooth muscle actin (SMA) antibody. Upon disruption of VEGF, 
      HCT116(VEGF-/-) xenografts had significantly decreased tumor microvessel 
      perfusion compared with their parental counterparts. Furthermore, HCT116(VEGF-/-) 
      xenografts mounted a tumor-reactive response to hypoxia, characterized by the 
      induction of hypoxia-inducible factor-1 (HIF-1) target genes. One highly induced 
      protein was DPP4, a measurable serum protein that has well-described roles in 
      cancer progression. In contrast, LS174T and MKN45 tumor xenografts had high 
      proportion of endothelial tubes that were covered by SMA+ pericytes. Upon 
      disruption of VEGF, LS174T(VEGF-/-) and MKN45(VEGF-/-) xenografts maintained 
      tumor microvessel perfusion. As such, there were no changes in intratumoral 
      hypoxia or HIF-1 alpha induction. Together, these data show that the extent of 
      tumor vessel response to angiogenic inhibition could be correlated with (a) the 
      preexisting coverage of tumor endothelial tubes with SMA+ pericytes and (b) 
      differential tumor induction of HIF-1 target genes. The data further show that 
      DPP4 is a novel marker of HIF-1 induction. Altogether, these preclinical findings 
      suggest novel clinical trials for predicting and monitoring tumor vessel 
      responses to antiangiogenic therapy.
FAU - Dang, Duyen T
AU  - Dang DT
AD  - Department of Internal Medicine, The University of Michigan Medical Center, Ann 
      Arbor, MI 48109, USA.
FAU - Chun, Sang Y
AU  - Chun SY
FAU - Burkitt, Kyunghee
AU  - Burkitt K
FAU - Abe, Masako
AU  - Abe M
FAU - Chen, Shaowei
AU  - Chen S
FAU - Havre, Pamela
AU  - Havre P
FAU - Mabjeesh, Nicola J
AU  - Mabjeesh NJ
FAU - Heath, Elisabeth I
AU  - Heath EI
FAU - Vogelzang, Nicholas J
AU  - Vogelzang NJ
FAU - Cruz-Correa, Marcia
AU  - Cruz-Correa M
FAU - Blayney, Douglas W
AU  - Blayney DW
FAU - Ensminger, William D
AU  - Ensminger WD
FAU - St Croix, Brad
AU  - St Croix B
FAU - Dang, Nam H
AU  - Dang NH
FAU - Dang, Long H
AU  - Dang LH
LA  - eng
GR  - K22CA111897/CA/NCI NIH HHS/United States
GR  - P30 CA46592/CA/NCI NIH HHS/United States
GR  - P30 DK34933/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 3.4.14.5 (DPP4 protein, human)
RN  - EC 3.4.14.5 (Dipeptidyl Peptidase 4)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Cell Hypoxia/genetics
MH  - Cell Line, Tumor
MH  - Dipeptidyl Peptidase 4/biosynthesis/genetics
MH  - Endothelium, Vascular/pathology
MH  - Female
MH  - Genetic Therapy
MH  - HCT116 Cells
MH  - HT29 Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/*genetics
MH  - Mice
MH  - Neoplasms/*blood supply/genetics/metabolism/*therapy
MH  - Neovascularization, Pathologic/genetics/metabolism/pathology/therapy
MH  - Vascular Endothelial Growth Factor A/*antagonists & inhibitors/genetics
MH  - Xenograft Model Antitumor Assays
EDAT- 2008/03/15 09:00
MHDA- 2008/04/10 09:00
CRDT- 2008/03/15 09:00
PHST- 2008/03/15 09:00 [pubmed]
PHST- 2008/04/10 09:00 [medline]
PHST- 2008/03/15 09:00 [entrez]
AID - 68/6/1872 [pii]
AID - 10.1158/0008-5472.CAN-07-1589 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Mar 15;68(6):1872-80. doi: 10.1158/0008-5472.CAN-07-1589.