Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival

Abstract

Summary 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 881-890 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2018, available online at http://www.idealibrary.com on http://www.bjcancer.comIn the present study we examined the expression patterns of HIF1α and of HIF2α in normal lung and in a series of non-smallcell lung carcinomas. The expression of HIFs was analysed in comparison with the microvessel density, with the expression of multiple angiogenic factors and receptors as well as with the expression of onco-proteins, previously shown to have a role in lung cancer. The prognostic role of HIF expression was also studied. MATERIALS AND METHODSWe examined 108 tumour samples from patients with early operable (T1,2-N0,1-M0 staged) non-small-cell lung cancer (72 squamous and 36 adenocarcinomas). 12 samples from normal lung obtained during thoracic surgery for reasons other than lung cancer were also examined. Histological diagnosis, grading and Nstage w...

Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

“…2,3,11,20 It has been shown to be overexpressed in tumors from various anatomic locations such as cervical squamous cell carcinomas, head and neck cancers and soft tissue tumors, HIF-1a in type I and type II endometrial adenocarcinoma V Pansare et al colon cancers, etc. 5,6,8,9,14 Tumor hypoxia through activation of angiogenesis helps in tumor progression and metastasis.…”

“…2 HIF-1a has been shown to be the driving force in upregulating angiogenic pathways in non-smallcell lung carcinoma and nasopharyngeal carcinoma. 20,24 In non-small-cell lung carcinoma, a strong association has been reported between HIF-1a accumulation in cancer cells, tumor microvessel density and the expression of multiple angiogenic factors, including VEGF. 16 Similarly Sivridis et al 11 have shown an association between HIF-1a overexpression and upregulation of VEGF in a cohort of stage I endometrioid-type endometrial adenocarcinoma.…”

“…[4][5][6][7][8][9][10][11]20 The negative impact of HIF-1a protein overexpression on prognosis has been shown in cancers of head and neck, cervix and soft tissue sarcomas. [5][6][7][8][9][10] It has been suggested that tumor hypoxia makes solid tumors resistant to radiation and chemotherapy.…”

Loss of expression and nuclear/cytoplasmic localization of the FOXP1 forkhead transcription factor are common events in early endometrial cancer: relationship with estrogen receptors and HIF-1α expression

“…19,20 A grading system reported in Table 2, that groups cases using both expression patterns, has been proposed and applied in a series of previous studies by our group. 15,[21][22][23] The percentage of tumor cells expressing the various antigens under investigation was assessed semiquantitatively at  200 magnification. The counts were performed on the entire tumor area in all available fields of view.…”

Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma

“…21 To date, a few studies, all based on a relatively small number of patients, have investigated the prognostic relevance of HIF-1 in human solid tumors, and none of those studies compared this relevance with that of HER-2/neu amplification. In patients with early cervical carcinoma (n ϭ 91 patients), 22 oropharyngeal carcinoma (n ϭ 98 patients), 23 oligodendrogliomas (n ϭ 51 patients), 24 and nonsmall cell lung carcinomas (n ϭ 108 patients), 25 high levels of HIF-1␣ predicted poor prognosis; however, the opposite was reported for lung carcinoma (n ϭ 55 patients) 26 and head and neck squamous cell carcinoma (n ϭ 69 patients), 27 whereas no effect on survival was noticed in patients with ovarian carcinoma (n ϭ 60 patients). 28 Therefore, studies based on adequate numbers of patients with long-term follow-up are needed to elucidate the prognostic relevance of HIF-1␣ in specific types of human malignancies.…”