Inhibition of Kaposi's sarcoma in vivo by fenretinide.
OBJECTIVE
We examined the effects of fenretinide [N-(4-hydroxyphenyl)retinamide; (4HPR)] on highly angiogenic Kaposi's sarcoma tumors in vivo and investigated the mechanisms involved for potential clinical applications.


METHODS
(CD-1)BR nude mice bearing KS-Imm cell tumors were randomized to receive 4HPR or vehicle until sacrifice. In vitro, KS-Imm and endothelial cells were treated with 4HPR to study the effects on proliferation, apoptosis, migration, and invasion; in vivo angiogenesis was evaluated in the Matrigel model. Angiogenesis-related and retinoid receptor molecules were examined at the mRNA and protein expression levels.


RESULTS
In vivo, 4HPR significantly (P<0.001) reduced growth of detectable Kaposi's sarcoma (KS) xenografts and inhibited angiogenesis in the Matrigel plug assay (P<0.04). In vitro, 4HPR affected KS-Imm and endothelial cell growth and KS-Imm migration and invasion. 4HPR invasion inhibition was associated with decreased release of matrix metalloprotease-2 and rapid reduction of vascular endothelial growth factor (VEGF) expression by KS cells and of vascular endothelial growth factor receptor 2 (VEGFR2) by KS and endothelial cells. Finally, 4HPR repression of angiogenesis was associated with a 4HPR-induced increase in retinoic acid receptor beta expression.


CONCLUSIONS
These data indicate that 4HPR inhibits KS tumor growth in vivo through a mechanism involving the modulation of angiogenesis-associated growth factors and their receptors on both tumor and endothelial cells. In addition, 4HPR inhibited invasion by decreasing of matrix metalloprotease-2 activity. Our results justify further studies to evaluate the utility of 4HPR as a chemopreventive or therapeutic agent in KS, a malignancy associated with immune suppression that has a high risk of recurrence with highly active antiretroviral therapy failure.
Ferrari
Nicoletta
N
Molecular Oncology Laboratory, the National Institute for Cancer Research, Genova, Italy.
Morini
Monica
M
Pfeffer
Ulrich
U
Minghelli
Simona
S
Noonan
Douglas M
DM
Albini
Adriana
A
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects; D017313:Fenretinide / Q000627:therapeutic use*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D017313:Fenretinide; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2; D020778:Matrix Metalloproteinase 2