Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival.
Kaposi's sarcoma (KS) is a highly vascular tumour and is the most common neoplasm associated with human immunodeficiency virus (HIV-1) infection. Growth factors, in particular vascular endothelial growth factor (VEGF), have been shown to play an important role in its development. The role of insulin-like growth factors (IGFs) in the pathophysiology of different tumours led us to evaluate the role of IGF system in KS. The IGF-I receptors (IGF-IR) were identified by immunohistochemistry in biopsies taken from patients with different AIDS/HIV-related KS stages and on KSIMM cells (an established KS-derived cell line). Insulin-like growth factor-I is a growth factor for KSIMM cells with a maximum increase of 3H-thymidine incorporation of 130 +/- 27.6% (P < 0.05) similar to that induced by VEGF and with which it is additive (281 +/- 13%) (P < 0.05). Moreover, specific blockade of the receptor (either by alpha IR3 antibody or by picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor) induced KSIMM apoptosis, suggesting that IGF-IR agonists (IGF-I and -II) mediate antiapoptotic signals for these cells. We were able to identify an autocrine loop essential for KSIMM cell survival in which IGF-II is the IGF-IR agonist secreted by the cells. In conclusion, IGF-I pathway inhibition is a promising therapeutical approach for KS tumours.
Catrina
S-B
SB
Department of Molecular Medicine, Diabetes Center Karolinska, Karolinska Hospital, M1:02, Karolinska Institutet, Stockholm, Sweden. Sergiu-Bogdan.Catrina@molmed.ki.se
Lewitt
M
M
Massambu
C
C
Dricu
A
A
Grünler
J
J
Axelson
M
M
Biberfeld
P
P
Brismar
K
K
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D013002:Somatomedins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D013002:Somatomedins; D042461:Vascular Endothelial Growth Factor A; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin