Hypoxia-inducible factor-1α and-2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

被引:68
作者
Rasheed, S. [2 ]
Harris, A. L. [3 ]
Tekkis, P. P. [2 ,4 ,5 ]
Turley, H. [3 ]
Silver, A. [6 ]
McDonald, P. J. [2 ]
Talbot, I. C. [1 ]
Glynne-Jones, R. [7 ]
Northover, J. M. A. [2 ]
Guenther, T. [1 ]
机构
[1] St Marks Hosp, Acad Dept Cellular Pathol, Harrow HA1 3UJ, Middx, England
[2] St Marks Hosp, Dept Surg, Harrow HA1 3UJ, Middx, England
[3] John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DU, England
[4] Univ London Imperial Coll Sci Technol & Med, Royal Marsden Hosp, Dept Surg Oncol & Technol, London, England
[5] Univ London Imperial Coll Sci Technol & Med, Chelsea & Westminster Hosp, Dept Surg Oncol & Technol, London, England
[6] Queen Marys Univ London, Inst Cell & Mol Sci, St Bartholomews & London Hosp, London, England
[7] Mt Vernon Hosp, Dept Oncol, Northwood HA6 2RN, Middx, England
关键词
rectal cancer; angiogenesis; hypoxia; HIF-1 alpha and HIF-2 alpha; microvessel density; INTRATUMORAL MICROVESSEL DENSITY; HUMAN BREAST-CANCER; FACTOR-L-ALPHA; COLORECTAL-CANCER; TUMOR ANGIOGENESIS; HIF-2-ALPHA EXPRESSION; CELL-PROLIFERATION; FACTOR; 1-ALPHA; HIF-1-ALPHA; CARCINOMA;
D O I
10.1038/sj.bjc.6605026
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1 alpha (HIF-1 alpha) and HIF-2 alpha protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n = 90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1 alpha and HIF-2 alpha expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1 alpha and HIF-2 alpha, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR) = 8.7, P<0.005) and decreased disease-free survival (HR = 4.7, P<0.005). hypoxia-inducible factor-1 alpha and -2 alpha were expressed in >50% of rectal cancers (HIF-1 alpha, 54%, 48/90; HIF-2 alpha, 64%, 58/90). HIF-1 alpha positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were shown between HIF-2 alpha expression and any pathological features, and HIF-1 alpha positivity had no effect on outcome. The study showed an independent association between HIF-1 alpha expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1 alpha, but not HIF-2 alpha, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management. British Journal of Cancer (2009) 100, 1666-1673. doi: 10.1038/sj.bjc.6605026 www.bjcancer.com (C) 2009 Cancer Research UK
引用
收藏
页码:1666 / 1673
页数:8
相关论文
共 51 条
[1]  
[Anonymous], 2006, CANC FACTS FIG
[2]   Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors [J].
Aprelikova, O ;
Chandramouli, GVR ;
Wood, M ;
Vasselli, JR ;
Riss, J ;
Maranchie, JK ;
Linehan, WM ;
Barrett, JC .
JOURNAL OF CELLULAR BIOCHEMISTRY, 2004, 92 (03) :491-501
[3]  
Birner P, 2000, CANCER RES, V60, P4693
[4]  
Blancher C, 2000, CANCER RES, V60, P7106
[5]  
BOSSI P, 1995, CANCER RES, V55, P5049
[6]   Role of HIF-1α or in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis [J].
Carmeliet, P ;
Dor, Y ;
Herbert, JM ;
Fukumura, D ;
Brusselmans, K ;
Dewerchin, M ;
Neeman, M ;
Bono, F ;
Abramovitch, R ;
Maxwell, P ;
Koch, CJ ;
Ratcliffe, P ;
Moons, L ;
Jain, RK ;
Collen, D ;
Keshet, E .
NATURE, 1998, 394 (6692) :485-490
[7]   The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells [J].
Carracedo, A ;
Lorente, M ;
Egia, A ;
Blázquez, C ;
García, S ;
Giroux, V ;
Malicet, C ;
Villuendas, R ;
Gironella, M ;
González-Feria, L ;
Piris, MA ;
Iovanna, JL ;
Guzmán, M ;
Velasco, G .
CANCER CELL, 2006, 9 (04) :301-312
[8]  
Chen Ying-Bo, 2004, Ai Zheng, V23, P1203
[9]   Tumor angiogenesis as a prognostic predictor in colorectal carcinoma with special reference to mode of metastasis and recurrence [J].
Choi, HJ ;
Hyun, MS ;
Jung, GJ ;
Kim, SS ;
Hong, SH .
ONCOLOGY, 1998, 55 (06) :575-581
[10]   Emerging therapies for rectal cancer [J].
Chua, Y. J. ;
Cunningham, D. .
COLORECTAL DISEASE, 2006, 8 :18-20