Molecular pathway for cancer metastasis to bone.
The molecular mechanism leading to the cancer metastasis to bone is poorly understood but yet determines prognosis and therapy. Here, we define a new molecular pathway that may account for the extraordinarily high osteotropism of prostate cancer. By using SPARC (secreted protein, acidic and rich in cysteine)-deficient mice and recombinant SPARC, we demonstrated that SPARC selectively supports the migration of highly metastatic relative to less metastatic prostate cancer cell lines to bone. Increased migration to SPARC can be traced to the activation of integrins alphaVbeta3 and alphaVbeta5 on tumor cells. Such activation is induced by an autocrine vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-2 loop on the tumor cells, which also supports the growth and proliferation of prostate cancer cells. A consequence of SPARC recognition by alphaVbeta5 is enhanced VEGF production. Thus, prostate cancer cells expressing VEGF/VEGFR-2 will activate alphaVbeta3 and alphaVbeta5 on their surface and use these integrins to migrate toward SPARC in bone. Within the bone environment, SPARC engagement of these integrins will stimulate growth of the tumor and further production of VEGF to support neoangiogenesis, thereby favoring the development of the metastatic tumor. Supporting this model, activated integrins were found to colocalize with VEGFR-2 in tissue samples of metastatic prostate tumors from patients.
De
Sarmishtha
S
Departments of Molecular Cardiology and Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Chen
Juhua
J
Narizhneva
Natalya V
NV
Heston
Warren
W
Brainard
Jennifer
J
Sage
E Helene
EH
Byzova
Tatiana V
TV
D000362:Agar / Q000494:pharmacology; D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology* / Q000556:secondary*; D001842:Bone and Bones; D002455:Cell Division; D002465:Cell Movement; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D015676:Osteonectin / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology; D019030:Receptors, Vitronectin / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D039302:Integrin alphaVbeta3; D016023:Integrins; D015676:Osteonectin; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C064660:integrin alphaVbeta5; D000362:Agar; D040301:Vascular Endothelial Growth Factor Receptor-2