title: Targeting of α(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer.
abstract: Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide α(v)-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that α(v)-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking α(v)-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms.
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Geertje
authors.initials: G
authors.lastname: van der Horst
authors.forename: Christel
authors.initials: C
authors.lastname: van den Hoogen
authors.forename: Jeroen T
authors.initials: JT
authors.lastname: Buijs
authors.forename: Henry
authors.initials: H
authors.lastname: Cheung
authors.forename: Henny
authors.initials: H
authors.lastname: Bloys
authors.forename: Rob C M
authors.initials: RC
authors.lastname: Pelger
authors.forename: Giocondo
authors.initials: G
authors.lastname: Lorenzon
authors.forename: Bertrand
authors.initials: B
authors.lastname: Heckmann
authors.forename: Jean
authors.initials: J
authors.lastname: Feyen
authors.forename: Philippe
authors.initials: P
authors.lastname: Pujuguet
authors.forename: Roland
authors.initials: R
authors.lastname: Blanque
authors.forename: Philippe
authors.initials: P
authors.lastname: Clément-Lacroix
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D051879:Twist-Related Protein 1 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D039564:Integrin alphaV; D051879:Twist-Related Protein 1