Could recombinant insulin compounds contribute to adenocarcinoma progression by stimulating local angiogenesis?
OBJECTIVE
Negative effects on the progression of adenocarcinomas by hyperinsulinaemia and the insulin analogue glargine (A21Gly,B31Arg,B32Arg human insulin) have recently been suggested. Most actions of this insulin analogue have hitherto been explained by direct stimulation of growth potential of neoplastic cells and by its IGF-1 related properties. However, insulin-stimulated angiogenesis could be an additional factor involved in tumour progression and clinical outcomes associated with cancer.


METHODS
Five types of human adenocarcinoma (breast, colon, pancreas, lung and kidney) were evaluated for the presence of insulin receptors (IRs) on angiogenic structures. In an in vitro angiogenesis assay, various commercially available insulin compounds were evaluated for their potential to increase capillary-like tube formation of human microvascular endothelial cells (hMVEC). Insulin compounds used were: human insulin, insulin lispro (B28Lys,B29Pro human insulin), insulin glargine and insulin detemir (B29Lys[e-tetradecanoyl],desB30 human insulin).


RESULTS
Insulin receptors were found to be strongly expressed on the endothelium of microvessels in all evaluated adenocarcinomas, in addition to variable expression on tumour cells. Low or no detectable expression of IRs was seen on microvessels in extratumoral stroma. Incubation with commercially available insulin compounds increased capillary-like tube formation of hMVEC in vitro.


CONCLUSIONS
Our results suggest that all tested insulin compounds may stimulate tumour growth by enhancing local angiogenesis. Future studies need to confirm the association between insulin therapy in type 2 diabetes and tumour progression.
Rensing
K L
KL
Department of Vascular Medicine, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. k.l.rensing@amc.uva.nl
Houttuijn Bloemendaal
F M
FM
Weijers
E M
EM
Richel
D J
DJ
Büller
H R
HR
Koolwijk
P
P
van der Loos
C M
CM
Twickler
Th B
TB
von der Thüsen
J H
JH
D000230:Adenocarcinoma / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000031:analogs & derivatives* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin