Age-related properties of the tumour vasculature in renal cell carcinoma.
OBJECTIVE
To assess whether ageing processes influence angiogenesis in renal cell carcinoma (RCC) we carried out a pilot study of vascular properties in a series of archival primary kidney tumours in patients of different ages.


METHODS
A cohort of patients with RCC was identified restrospectively, with an age range of 35-84 years. Paraffin-embedded, formalin-fixed sections of surgical tumour specimens were stained for endothelial (CD31, von Willebrand factor [vWF]), pericyte (alpha smooth muscle actin [SMA]) and leucocytic (CD45) markers, as well as for proliferative (Ki67) and angiogenic activity (tumour endothelial markers [TEMs], delta-like 4 [Dll4], Dll1, endothelial nitric oxide synthase [eNOS]). Vascular properties were compared between patients above and below 65 years of age.


RESULTS
Microvascular density (MVD) within capillary hot spots was generally higher in patients with non-metastatic clear-cell RCC (ccRCC; n = 21) than in those with metastatic RCC (mRCC; n= 9). Patients with ccRCC who were more than 65 years old showed significantly higher MVD than their younger (< 65 years) counterparts. There were dividing (Ki67-positive) endothelial and mural cells in both small (< 20 µm) capillary and large (> 20 µm), pre-capillary vessels, suggesting the involvement of both angiogenic and remodelling/arteriogenic processes. Tumour endothelial markers (TEM1, TEM7, TEM8), Notch ligands (Dll1, Dll4), and other molecular characteristics (eNOS) were analysed. Age-related differences were observed in the frequency of pre-capillary vessels expressing Dll1, which was significantly higher in tumours of younger patients (< 65 years), while eNOS was more prevalent among capillaries associated with ccRCC in older patients (>6 5 years).


CONCLUSIONS
The results of the present study suggest that age influences the structural and molecular properties of the tumour vasculature in ccRCC. We postulate that vascular ageing could also be relevant in the context of anti-angiogenic therapy.
Meehan
Brian
B
Montreal Children's Hospital Research Institute, McGill University, Montreal, QC, Canada.
Appu
Sree
S
St Croix
Brad
B
Rak-Poznanska
Krystyna
K
Klotz
Laurence
L
Rak
Janusz
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000473:pathology / Q000556:secondary; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*
J Clin Oncol. 2009 Jul 1;27(19):3225-34
19470934
Urology. 1998 May;51(5):693-6
9610581
Int J Urol. 1998 Mar;5(2):119-23
9559835
Endothelium. 2003;10(4-5):207-16
14660080
Br J Urol. 1997 Sep;80(3):401-4
9313657
Nat Rev Cancer. 2008 Nov;8(11):865-73
18923434
Nephron Exp Nephrol. 2005;101(3):e95-9
16043968
Nat Rev Cancer. 2005 Jun;5(6):436-46
15928674
Circulation. 2003 Jul 29;108(4):457-63
12860902
Pathology. 2009;41(4):335-41
19404845
Nat Clin Pract Cardiovasc Med. 2006 Feb;3(2):94-101
16446778
Clin Cancer Res. 2001 Mar;7(3):533-7
11297244
Nat Rev Cancer. 2007 May;7(5):327-31
17457300
Nat Rev Cancer. 2005 Aug;5(8):655-62
16056261
Science. 2000 Aug 18;289(5482):1197-202
10947988
N Engl J Med. 1991 Jan 3;324(1):1-8
1701519
Circulation. 2004 Aug 31;110(9):1148-55
15302783
Am J Physiol Cell Physiol. 2006 Nov;291(5):C803-16
16738003
Clin Cancer Res. 2007 Jan 1;13(1):161-9
17200351
Cancer Res. 1984 Dec;44(12 Pt 1):5677-80
6388828
Nat Med. 2000 Apr;6(4):389-95
10742145
Ann Pathol. 2008 Oct;28(5):374-80
19068392
Med Oncol. 2010 Dec;27(4):1359-70
20043216
Int Urol Nephrol. 2007;39(3):691-8
17180739
Am J Pathol. 2007 Oct;171(4):1342-51
17823292
Angiogenesis. 2004;7(2):143-56
15516835
Mol Cancer Ther. 2008 Aug;7(8):2536-46
18723498
Nephron Physiol. 2007;106(2):p32-7
17570946
Sci Aging Knowledge Environ. 2004 Feb 18;2004(7):pe7
14973174
Int J Urol. 2004 Nov;11(11):948-53
15509196
J Natl Cancer Inst. 1994 Sep 7;86(17):1303-14
7520508
Cancer. 1997 Nov 1;80(9):1768-75
9351546
Angiogenesis. 2009;12(1):69-79
19212818
J Biol Chem. 2000 Sep 22;275(38):29643-7
10882714
Pol J Pathol. 2008;59(2):107-15
18669177
Am J Pathol. 1993 Nov;143(5):1255-62
8238242
Urology. 1995 Jul;46(1):27-30
7604476
FASEB J. 2000 May;14(7):871-6
10783140
Breast Cancer Res. 2003;5(2):83-8
12631386
Angiogenesis. 2001;4(4):247-57
12197469
Circ Res. 2007 Feb 16;100(3):363-71
17234965
Cancer Res. 2005 Oct 1;65(19):8690-7
16204037
N Engl J Med. 2008 May 8;358(19):2039-49
18463380
Nat Cell Biol. 2008 May;10(5):619-24
18425114
BJU Int. 2008 Mar;101(6):758-64
18070177
Cancer Res. 2002 Jan 15;62(2):552-9
11809709
Nature. 1999 Oct 14;401(6754):670-7
10537105
Acta Biochim Biophys Sin (Shanghai). 2008 Aug;40(8):681-92
18685784
N Engl J Med. 2007 Jan 11;356(2):125-34
17215530
Cancer Res. 2007 Feb 15;67(4):1407-10
17308075
Nat Rev Drug Discov. 2004 May;3(5):391-400
15136787
Am J Pathol. 2008 Feb;172(2):486-94
18187565
Physiology (Bethesda). 2006 Dec;21:388-95
17119151