Evidence of increased microvessel density and activation of the hypoxia pathway in turnours from the hereditary leiomyomatosis and renal cell cancer syndrome

被引:73
作者
Pollard, P
Wortham, N
Barclay, E
Alam, A
Elia, G
Manek, S
Poulsom, R
Tomlinson, I
机构
[1] Canc Res UK, Mol & Populat Genet Lab, London WC2A 3PX, England
[2] Canc Res UK, Histopathol Lab, London WC2A 3PX, England
[3] John Radcliffe Hosp, Dept Cellular Pathol, Oxford OX3 9DZ, England
[4] Canc Res UK, London Res Inst, Situ Hybridisat Serv, London WC2A 3PX, England
关键词
microvessel density; hypoxia; hereditary leiomyomatosis and renal cell cancer syndrome;
D O I
10.1002/path.1686
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The Mendelian tumour syndromes hereditary leiomyomatosis and renal cell cancer (HLRCQ and hereditary paragangliomatosis with phaeochromocytomas (HPGL) result from mutations in nuclear genes (FH and SDHB/CID, respectively) that encode Krebs cycle enzymes. HPGL tumours are highly vascular and there is evidence that inactivation of SDH leads to activation of the hypoxia/angiogenesis pathway. In contrast, uterine leiomyomas are not generally regarded as particularly vascular lesions. In order to test the possibility that activation of the hypoxia/angiogenesis pathway contributes to tumourigenesis in HLRCC, increased vascularity and hypoxia pathway activation were searched for in HLRCC tumours. Microvessel density was markedly higher in uterine leiomyomas from HLRCC than in the surrounding myometrium; it was notable that sporadic uterine leiomyomas were actually less vascular than normal myometrium. In HLRCC tumours, there was increased expression of transcripts from the hypoxia-responsive genes vascular endothelial growth factor (VEGF) and BNIP3; sporadic uterine leiomyomas did not show these changes. All uterine leiomyomas showed decreased expression of thrombospondin 1. Although sporadic and HLRCC uterine leiomyomas appear to have identical morphology, their pathways of tumourigenesis may be fundamentally different. As is the case in HPGL, it is probable that failure of the Krebs cycle in HLRCC tumours causes inappropriate signalling that the cell is in a hypoxic state, leading to angiogenesis and perhaps directly to clonal expansion and tumour growth through some uncharacterized, cell-autonomous effect. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.
引用
收藏
页码:41 / 49
页数:9
相关论文
共 35 条
[1]   Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma [J].
Astuti, D ;
Latif, F ;
Dallol, A ;
Dahia, PLM ;
Douglas, F ;
George, E ;
Sköldberg, F ;
Husebye, ES ;
Eng, C ;
Maher, ER .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (01) :49-54
[2]   Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas [J].
Barker, KT ;
Bevan, S ;
Wang, R ;
Lu, YJ ;
Flanagan, AM ;
Bridge, JA ;
Fisher, C ;
Finlayson, CJ ;
Shipley, J ;
Houlston, RS .
BRITISH JOURNAL OF CANCER, 2002, 87 (04) :446-448
[3]   Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma [J].
Baysal, BE ;
Ferrell, RE ;
Willett-Brozick, JE ;
Lawrence, EC ;
Myssiorek, D ;
Bosch, A ;
van der Mey, A ;
Taschner, PEM ;
Rubinstein, WS ;
Myers, EN ;
Richard, CW ;
Cornelisse, CJ ;
Devilee, P ;
Devlin, B .
SCIENCE, 2000, 287 (5454) :848-851
[4]   Hereditary paraganglioma target's diverse paraganglia [J].
Baysal, BE .
JOURNAL OF MEDICAL GENETICS, 2002, 39 (09) :617-622
[5]   VASCULAR-PERMEABILITY FACTOR (VASCULAR ENDOTHELIAL GROWTH-FACTOR) GENE IS EXPRESSED DIFFERENTIALLY IN NORMAL-TISSUES, MACROPHAGES, AND TUMORS [J].
BERSE, B ;
BROWN, LF ;
VANDEWATER, L ;
DVORAK, HF ;
SENGER, DR .
MOLECULAR BIOLOGY OF THE CELL, 1992, 3 (02) :211-220
[6]   TSC2 regulates VEGF through mTOR-dependent and -independent pathways [J].
Brugarolas, JB ;
Vazquez, F ;
Reddy, A ;
Sellers, WR ;
Kaelin, WG .
CANCER CELL, 2003, 4 (02) :147-158
[7]   Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia [J].
Bruick, RK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (16) :9082-9087
[8]   The cell biology of thrombospondin-1 [J].
Chen, H ;
Herndon, ME ;
Lawler, J .
MATRIX BIOLOGY, 2000, 19 (07) :597-614
[9]   von Hippel-Lindau disease: Clinical and molecular perspectives [J].
Clifford, SC ;
Maher, ER .
ADVANCES IN CANCER RESEARCH, VOL 82, 2001, 82 :85-105
[10]   A role for mitochondrial enzymes in inherited neoplasia and beyond [J].
Eng, C ;
Kiuru, M ;
Fernandez, MJ ;
Aaltonen, LA .
NATURE REVIEWS CANCER, 2003, 3 (03) :193-202