| Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy. | |
MedLine Citation:
|
PMID: 21724587 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
VEGF receptor-2 (VEGFR-2 or kinase insert domain receptor; KDR) is a known endothelial target also expressed in NSCLC tumor cells. We investigated the association between alterations in the KDR gene and clinical outcome in patients with resected non-small-cell lung carcinoma (NSCLC; n = 248). KDR copy number gains (CNG), measured by quantitative PCR and fluorescence in situ hybridization, were detected in 32% of tumors and associated with significantly higher KDR protein and higher microvessel density than tumors without CNGs. KDR CNGs were also associated with significantly increased risk of death (HR = 5.16; P = 0.003) in patients receiving adjuvant platinum-based chemotherapy, but no differences were observed in patients not receiving adjuvant therapy. To investigate potential mechanisms for these associations, we assessed NSCLC cell lines and found that KDR CNGs were significantly associated with in vitro resistance to platinum chemotherapy as well as increased levels of nuclear hypoxia inducible factor-1α (HIF-1α) in both NSCLC tumor specimens and cell lines. Furthermore, KDR knockdown experiments using small interfering RNA reduced platinum resistance, cell migration, and HIF-1α levels in cells bearing KDR CNGs, providing evidence for direct involvement of KDR. No KDR mutations were detected in exons 7, 11, and 21 by PCR-based sequencing; however, two variant single nucleotide polymorphism genotypes were associated with favorable overall survival in adenocarcinoma patients. Our findings suggest that tumor cell KDR CNGs may promote a more malignant phenotype including increased chemoresistance, angiogenesis, and HIF-1α levels, and that KDR CNGs may be a useful biomarker for identifying patients at high risk for recurrence after adjuvant therapy, a group that may benefit from VEGFR-2 blockade. |
Authors:
|
Fei Yang; Ximing Tang; Erick Riquelme; Carmen Behrens; Monique B Nilsson; Uma Giri; Marileila Varella-Garcia; Lauren A Byers; Heather Y Lin; Jing Wang; Maria G Raso; Luc Girard; Kevin Coombes; J Jack Lee; Roy S Herbst; John D Minna; John V Heymach; Ignacio I Wistuba |
Related Documents
:
|
21741077 - High beclin 1 expression defines a poor prognosis in endometrial adenocarcinomas. 21625617 - Inactivation of chk2 and mus81 leads to impaired lymphocytes development, reduced genom... 150557 - The steroid profile of a virilizing ovarian tumor. 21327457 - Overexpression of long non-coding rna hotair predicts tumor recurrence in hepatocellula... 15746047 - Prognostic effect of epidermal growth factor receptor and egfrviii in glioblastoma mult... 11857377 - Concurrent overexpression of ets-1 and c-met correlates with a phenotype of high cellul... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-07-01 |
Journal Detail:
|
Title: Cancer research Volume: 71 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2011 Aug |
Date Detail:
|
Created Date: 2011-08-15 Completed Date: 2011-10-13 Revised Date: 2014-09-08 |
Medline Journal Info:
|
Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
|
Languages: eng Pagination: 5512-21 Citation Subset: IM |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Carcinoma, Non-Small-Cell Lung
/
drug therapy*,
genetics Chemotherapy, Adjuvant* Drug Resistance, Neoplasm Gene Dosage* Humans In Situ Hybridization, Fluorescence Lung Neoplasms / drug therapy*, genetics Polymerase Chain Reaction Polymorphism, Single Nucleotide Survival Rate Vascular Endothelial Growth Factor Receptor-2 / genetics* |
| Grant Support | |
ID/Acronym/Agency:
|
CA-16672/CA/NCI NIH HHS; P30 CA016672-34/CA/NCI NIH HHS; P50 CA058187/CA/NCI NIH HHS; P50 CA058187-16/CA/NCI NIH HHS; P50 CA070907/CA/NCI NIH HHS; P50 CA070907-15/CA/NCI NIH HHS; P50CA58187/CA/NCI NIH HHS; P50CA70907/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Overexpression of MBD2 in glioblastoma maintains epigenetic silencing and inhibits the antiangiogeni...
Next Document: GPR56 Regulates VEGF production and angiogenesis during melanoma progression.