title: CXCR4 pharmacogical inhibition reduces bone and soft tissue metastatic burden by affecting tumor growth and tumorigenic potential in prostate cancer preclinical models.
abstract: BACKGROUND
  The majority of prostate cancer (Pca) patient morbidity can be attributed to bone metastatic events, which poses a significant clinical obstacle. Therefore, a better understanding of this phenomenon is imperative and might help to develop novel therapeutic strategies. Stromal cell-derived factor 1α (SDF-1α) and its receptor CXCR4 have been implicated as regulators of bone resorption and bone metastatic development, suggesting that agents able to suppress this signaling pathway may be used as pharmacological treatments. In this study we studied if two CXCR4 receptor antagonists, Plerixafor and CTE9908, may affect bone metastatic disease induced by Pca in preclinical experimental models
  
  
  METHODS
  To verify the hypothesis that CXCR4 inhibition affects Pca metastatic disease, selective CXCR4 compounds, Plerixafor, and CTE9908, were tested in preclinical models known to generate bone lesions. Additionally, the expression levels of CXCR4 and SDF-1α were analyzed in a number of human tissues derived from primary tumors, lymph-nodes and osseous metastases of Pca as well as in a wide panel of human Pca cell lines to non-tumorigenic and tumorigenic phenotype.
  
  
  RESULTS
  Bone-derived Pca cells express higher CXCR4 levels than other Pca cell lines. This differential expression was also observed in human Pca samples. In vitro evidence supports the hypothesis that factors produced by bone microenvironment differentially sustain CXCR4 and SDF1-α expression with respect to prostate microenvironment determining increased efficacy toward Plerixafor. The use of SDF1-α neutralizing antibodies greatly reduced the increase of CXCR4 expression in cells co-cultured with bone stromal cells (BMSc) and to a lesser extent in cells co-cultured with prostate stromal cells (HPSc) and partially reduced SDF1-α Plerixafor efficacy. SDF-1α induced tumor cell migration and invasion, as well as MMP-9, MMP-2, and uPA expression, which were reduced by Plerixafor. The incidence of X-ray detectable bone lesions was significantly reduced following Plerixafor and CTE9908 treatment Kaplan-Meier probability plots showed a significant improvement in the overall survival of mice treated with Plerixafor and CTE9908. The reduced intra-osseous growth of PC3 and PCb2 tumor cells after intratibial injection, as a result of Plerixafor and CTE9908 treatment, correlated with decreased osteolysis and serum levels of both mTRAP and type I collagen fragments (CTX), which were significantly lower with respect to controls.
  
  
  CONCLUSIONS
  Our report provides novel information on the potential activity of CXCR4 inhibitors on the formation and progression of Pca bone and soft tissue metastases and supports a biological rationale for the use of these inhibitors in men at high risk to develop clinically evident bone lesions.
authors.affiliation: Division of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.|Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mancini
authors.affiliation: Department of Life, Health and Environmental Sciences, L'Aquila, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Muzi
authors.affiliation: Pathology Department, San Salvatore Hospital L'Aquila, L'Aquila, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ventura
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Molecular Pathology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Leda
authors.initials: L
authors.lastname: Biordi
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Molecular Pathology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Ricevuto
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Human Anatomy, L'Aquila, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pompili
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mattei
authors.affiliation: Division of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.|Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Di Cesare
authors.affiliation: Department of Systems Medicine, University of Tor Vergata, Roma, Italy.
authors.forename: Emmanuele A
authors.initials: EA
authors.lastname: Jannini
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D001596:Benzylamines; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000556:secondary*; D002448:Cell Adhesion; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D018920:Coculture Techniques; D000080027:Cyclams; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001596:Benzylamines; C540323:CTCE-9908; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D010455:Peptides; D019718:Receptors, CXCR4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C088327:plerixafor
keywords: CXCR4; Plerixafor; bone metastases; prostate cancer