Targeting ECM-integrin interaction with liposome-encapsulated small interfering RNAs inhibits the growth of human prostate cancer in a bone xenograft imaging model.
The intricate intracellular communication between stromal and epithelial cells, which involves cell-cell-, cell-insoluble extracellular matrix- (ECM), and cell-soluble factor-mediated signaling processes, is an attractive target for therapeutic intervention in hormone-refractory and bone-metastatic prostate cancer. In the present study we demonstrated that androgen-independent PC3 prostate cancer cells adhered to and migrated on vitronectin (VN), a major noncollagenous ECM in mature bone, through the expression of alphav-containing integrin receptors alphavbeta1 and alphavbeta5 on the cell surface, as determined by antibody function blocking assay and flow cytometry analysis. Small interfering RNAs (siRNAs) targeting human integrin alphav markedly reduced their respective mRNA and protein expression in cells, resulting in nearly complete reduction in VN-mediated cancer progression in vitro. In vivo quantitative bioluminescence analysis of human prostate cancer bone xenografts demonstrated for the first time that intratumoral administration of liposome-encapsulated human alphav-siRNAs significantly inhibits the growth of luciferase-tagged PC3 tumors in skeleton, which was associated with decreased integrin alphav expression and increased apoptosis in tumor cells. This integrin-based gene therapy is particularly suitable for the treatment of prostate cancer bone metastasis.
Bisanz
Kristen
K
Molecular Urology and Therapeutics Program, Department of Urology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Yu
Jie
J
Edlund
Magnus
M
Spohn
Bill
B
Hung
Mien-Chie
MC
Chung
Leland W K
LW
Hsieh
Chia-Ling
CL
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary* / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D020868:Gene Silencing / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D039564:Integrin alphaV / Q000187:drug effects / Q000378:metabolism*; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D019096:Vitronectin / Q000378:metabolism*
D039564:Integrin alphaV; D008081:Liposomes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019096:Vitronectin