Targeting ECM–Integrin Interaction with Liposome-Encapsulated Small Interfering RNAs Inhibits the Growth of Human Prostate Cancer in a Bone Xenograft Imaging Model

Abstract

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.

Advantages of bioluminescence imaging to follow siRNA or chemotherapeutic treatments in osteosarcoma preclinical models

“…40,41 In one study using siRNA, a soil-dependent effect was observed. Bisanz et al 18 reported a strong effect of siRNA directed against integrin subunits combined with liposome on the growth of human prostate tumor in bone, but not on subcutaneaous tumor growth. Similar site-dependent effects can be expected with siRNA directed against RANKL, the major cytokine involved in the vicious cycle between osteolysis and bone tumor progression.…”

“…Moreover, these studies have predominantly decreased the expression of genes associated with cell cycle. [18][19][20][21] In osteosarcomas, one way to evaluate the therapeutic potential of small interfering RNA (siRNA) would be to target expression of RANKL in comparison with its blockage by antibody. However, the main challenge for the successful use of siRNA in vivo is to achieve an efficient delivery of these molecules to the target tissue without off-target effects.…”

Clinical Translation of a Dual Integrin αvβ3– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, 68Ga-BBN-RGD

“…Bisanz et al (32) have illustrated a positive role of a v integrins on prostate tumor survival in the bone. Integrin a v b 3 activation on tumor cells is essential for the recognition of key bone-specific matrix proteins, suggesting that the a v b 3 integrin modulates prostate cancer growth in distant metastasis (33).…”

Chemical and Biochemical Basis of Cell-Bone Matrix Interaction in Health and Disease

“…Several in vivo studies also support the view. For instance, intratumoral administration of liposome-encapsulated human α v -siRNA significantly inhibits the growth of PC-3 prostate tumor cells in skeleton, which was associated with decreased integrin α v subunit expression and increased apoptosis in tumor cells [106]. Another recent mouse model study demonstrated that the expression of fully functional α v β 3 promoted tumor growth in bone, whereas inactive mutants failed to do so [104], further suggesting that integrin α v β 3 may play a role in prostate cancer cell-bone interaction.…”