Hypoxia inducible factor-1 alpha and vascular endothelial growth factor in biopsies of small cell lung carcinoma.
Neoangiogenesis has been documented in small cell lung carcinoma (SCLC). In addition, antiangiogenic therapies are being tested in clinical trials that involve SCLC. However, study of the underlying mechanisms has been performed almost exclusively in cell lines. In the current study, we immunostained 30 biopsy samples of SCLC with antibodies to hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), vascular endothelial growth factor-receptor 1 (VEGF-R1/flt-1) and vascular endothelial growth factor-receptor 2 (VEGF-R1/flk-1). The immunoreactivity was analyzed using a bivariate Spearman correlation test and linear regression analysis. We found significant correlation between HIF-1 alpha nuclear staining and VEGF staining. Moreover HIF-1 alpha+/VEGF+ cases were associated with poor survival. We also found a positive correlation between VEGF and VEGF-R2 expression. We suggest that a HIF-1 alpha/VEGF angiogenic pathway may exist in vivo in SCLC, similar to that in non-SCLC. Our data also suggest a potential VEGF/VEGFR-2 autocrine pathway in SCLC. The inclusion of novel inhibitors to HIF-1 alpha and other factors may optimize antiangiogenic interventions in SCLC.
Ioannou
M
M
Department of Pathology, Medical School, University of Thessaly, Mezourlo, Larissa, 41110, Greece.
Papamichali
R
R
Kouvaras
E
E
Mylonis
I
I
Vageli
D
D
Kerenidou
T
T
Barbanis
S
S
Daponte
A
A
Simos
G
G
Gourgoulianis
K
K
Koukoulis
G K
GK
D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008175:Lung Neoplasms / Q000098:blood supply / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D018570:Risk Assessment; D055752:Small Cell Lung Carcinoma / Q000098:blood supply / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
Genes Dev. 2000 Jan 1;14(1):34-44
10640274
J Biol Chem. 2000 May 26;275(21):15905-11
10748050
Cancer Res. 1999 Nov 15;59(22):5830-5
10582706
Mol Cancer Ther. 2006 Jun;5(6):1415-22
16818499
Blood. 1996 Apr 15;87(8):3336-43
8605350
Neoplasia. 2001 Jan-Feb;3(1):80-7
11326319
Nature. 1995 Jun 15;375(6532):577-81
7540725
Science. 2001 Apr 20;292(5516):464-8
11292862
J Biol Chem. 1996 Jul 26;271(30):17629-34
8663424
Cancer Res. 1995 Oct 15;55(20):4575-80
7553632
Crit Rev Oncol Hematol. 2004 Jul;51(1):45-53
15207253
Med Oncol. 2008;25(4):394-9
18317954
Clin Cancer Res. 1996 Aug;2(8):1411-6
9816315
Cancer Res. 2000 Mar 15;60(6):1541-5
10749120
Mol Cell Biol. 1996 Sep;16(9):4604-13
8756616
Nature. 1999 May 20;399(6733):271-5
10353251
Biochem Biophys Res Commun. 2000 Apr 2;270(1):108-11
10733912
Free Radic Res. 2006 Aug;40(8):847-56
17015263
Cell Physiol Biochem. 2007;20(6):995-1006
17982282
Cytokine Growth Factor Rev. 2005 Feb;16(1):77-89
15733833
Cancer Res. 1995 Dec 15;55(24):6161-5
8521408
EMBO J. 1998 Jun 1;17(11):3005-15
9606183
Cancer Res. 1996 May 15;56(10):2299-301
8625303
Blood. 2001 Sep 15;98(6):1904-13
11535528
Am J Surg Pathol. 1995 Jun;19(6):642-52
7538732
Histol Histopathol. 2007 May;22(5):559-72
17330811
Br J Cancer. 2001 Sep 14;85(6):881-90
11556841
Genes Dev. 1998 Jan 15;12(2):149-62
9436976
Eur J Cardiothorac Surg. 2006 Jun;29(6):891-5
16675263
Cancer Res. 2001 Apr 1;61(7):2911-6
11306467
Eur Urol. 2004 Aug;46(2):200-8
15245814
Ai Zheng. 2002 Mar;21(3):254-8
12451989
Cancer Res. 2000 Sep 1;60(17):4693-6
10987269
Chest. 1997 Oct;112(4 Suppl):251S-258S
9337299
Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579-86
1417831
Nature. 1998 Jul 30;394(6692):485-90
9697772
Blood. 1993 Dec 15;82(12):3610-5
8260699
J Biol Chem. 1994 Oct 28;269(43):26988-95
7929439
Clin Cancer Res. 2003 Jan;9(1):433-40
12538497
Science. 1992 Feb 21;255(5047):989-91
1312256
Oncogene. 1997 May 22;14(20):2475-83
9188862
Eur J Cardiothorac Surg. 2002 Jun;21(6):1105-10
12048093
Am J Pathol. 2000 Aug;157(2):411-21
10934146
Cell. 1998 Mar 20;92(6):735-45
9529250
Cell Mol Life Sci. 2007 Aug;64(16):2170-80
17514355