Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival
Alexandra Giatromanolaki,M I Koukourakis,Efthimios Sivridis,Helen Turley,Kate L. Talks,Francesco Pezzella,K C Gatter,Adrian L. Harris +7 more
Reads0
Chats0
TLDR
It is concluded that HIF1α and HIF2α overexpression is a common event in NSCLC, which is related to the up-regulation of various angiogenic factors and with poor prognosis.Abstract:
Hypoxia inducible factors HIF1α and HIF2α are important proteins involved in the regulation of the transcription of a variety of genes related to erythropoiesis, glycolysis and angiogenesis. Hypoxic stimulation results in rapid increase of the HIF1α and 2α protein levels, as a consequence of a redox-sensitive stabilization. The HIFαs enter the nucleus, heterodimerize with the HIF1β protein, and bind to DNA at the hypoxia response elements (HREs) of target genes. In this study we evaluated the immunohistochemical expression of these proteins in 108 tissue samples from non-small-cell lung cancer (NSCLC) and in normal lung tissues. Both proteins showed a mixed cytoplasmic/nuclear pattern of expression in cancer cells, tumoural vessels and tumour-infiltrating macrophages, as well as in areas of metaplasia, while normal lung components showed negative or very weak cytoplasmic staining. Positive HIF1α and HIF2α expression was noted in 68/108 (62%) and in 54/108 (50%) of cases respectively. Correlation analysis of HIF2α expression with HIF1α expression showed a significant association (P < 0.0001, r = 0.44). A strong association of the expression of both proteins with the angiogenic factors VEGF (P < 0.004), PD-ECGF (P < 0.003) and bFGF (P < 0.04) was noted. HIF1α correlated with the expression of bek-bFGF receptor expression (P = 0.01), while HIF2α was associated with intense VEGF/KDR-activated vascularization (P = 0.002). HIF2α protein was less frequently expressed in cases with a medium microvessel density (MVD); a high rate of expression was noted in cases with both low and high MVD (P = 0.006). Analysis of overall survival showed that HIF2α expression was related to poor outcome (P = 0.008), even in the group of patients with low MVD (P = 0.009). HIF1α expression was marginally associated with poor prognosis (P = 0.08). In multivariate analysis HIF2α expression was an independent prognostic indicator (P = 0.006, t-ratio 2.7). We conclude that HIF1α and HIF2α overexpression is a common event in NSCLC, which is related to the up-regulation of various angiogenic factors and with poor prognosis. Targeting the HIF pathway may prove of importance in the treatment of NSCLC. © 2001 Cancer Research Campaignhttp://www.bjcancer.comread more
Citations
More filters
Journal ArticleDOI
Targeting HIF-1 for cancer therapy
TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.
Journal ArticleDOI
Hypoxia in cancer: significance and impact on clinical outcome
Peter Vaupel,Arnulf Mayer +1 more
TL;DR: In this article, the authors suggest that hypoxia is prognostic for survival and local control in head and neck cancers, and use endogenous proteins (e.g., HIF-1α, GLUT-1, CA IX) or exogenous bioreductive drugs.
Journal ArticleDOI
Molecular origins of cancer: Lung cancer
TL;DR: From the Departments of Thoracic/Head and Neck Medical Oncology and Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston.
Journal ArticleDOI
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
TL;DR: This review summarizes the current state of knowledge regarding the molecular mechanisms by which Hif-1 contributes to cancer progression, focusing on clinical data associating increased HIF-1 levels with patient mortality and pharmacological data showing anticancer effects of H IF-1 inhibitors in mouse models of human cancer.
Journal ArticleDOI
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
TL;DR: A more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.
References
More filters
Journal ArticleDOI
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Patrick H. Maxwell,Michael S. Wiesener,Gin-Wen Chang,Steven C. Clifford,Emma C. Vaux,Matthew Edward Cockman,Charles C. Wykoff,Christopher W. Pugh,Eamonn R. Maher,Peter J. Ratcliffe,Peter J. Ratcliffe +10 more
TL;DR: It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.
Journal ArticleDOI
Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.
Jo A. Forsythe,Bing-Hua Jiang,Narayan V. Iyer,Faton Agani,Sandra W. Leung,Robert D. Koos,Gregg L. Semenza +6 more
TL;DR: HIF-1 is implicate in the activation of VEGF transcription in hypoxic cells and this work demonstrates the involvement of Hif-1 in theactivation of V EGF transcription.
Journal ArticleDOI
A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.
Gregg L. Semenza,Guang L. Wang +1 more
TL;DR: A functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by Hypoxia via de novo protein synthesis.
Journal ArticleDOI
Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.
Peter Carmeliet,Yuval Dor,Jean-Marc Herbert,Dai Fukumura,Koen Brusselmans,Mieke Dewerchin,Michal Neeman,Françoise Bono,Rinat Abramovitch,Patrick H. Maxwell,Cameron J. Koch,Peter J. Ratcliffe,Lieve Moons,Rakesh K. Jain,Desire Collen,Eli Keshert +15 more
TL;DR: It is shown that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (Hif-1α+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1 α genes (HIF- 1α−/−), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients.
Journal Article
Overexpression of Hypoxia-inducible Factor 1α in Common Human Cancers and Their Metastases
Hua Zhong,Angelo M. De Marzo,Erik Laughner,Michael Lim,David A Hilton,David Zagzag,Peter Buechler,William B. Isaacs,Gregg L. Semenza,Jonathan W. Simons +9 more
TL;DR: The first clinical data indicating that HIF-1alpha may play an important role in human cancer progression are provided, indicating adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality.