title: Tasquinimod inhibits prostate cancer growth in bone through alterations in the bone microenvironment.
abstract: BACKGROUND
  Tasquinimod (ABR-215050) is an orally active quinoline-3-carboxamide analog that inhibits occurrence of experimental metastasis and delays disease progression of castration resistant prostate cancer in humans. Its mechanism of action is not fully elucidated, but previous studies show immunomodulatory and anti-angiogenic effects. The aim of the present study was to investigate the tumor inhibiting effect of tasquinimod in bone of castrated mice as well as to elucidate its working mechanism related to bone microenvironment.
  
  
  METHODS
  Effects of tasquinimod on prostate cancer metastasis to bone was studied in an intratibial xenograft model. Animals were treated with tasquinimod and tumor establishment and growth, immunological status, as well as markers for bone remodeling were analyzed. Direct effects of tasquinimod on osteoblasts were studied in vitro.
  
  
  RESULTS
  Establishment and growth of tumors in the bone after intratibial implantation in castrated mice was suppressed by tasquinimod treatment. The treatment effect was linked to decreased potential for immunosuppression in the pre-metastatic niche in bone (lower levels of CD206 and Arg1 expression in combination with increased iNOS expression) as well as in the tumor microenvironment (less Gr1 and CD206 staining). The shift to a pro-inflammatory, anti-tumorigenic milieu was also reflected in serum by increased levels of IFN-γ, CCL4, IL-5, LIX, IP-10, and MCP-1 as well as decreased TGF-β. Tasquinimod treatment also affected expression of factors involved in the pre-metastatic niche in the bone microenvironment (Lox, Cdh2, Cdh11, and Cxcl12). In addition, tasquinimod treatment caused a decreased osteogenic response indicated by decreased expression of Ocn, Runx2, and Col1a2 and increased expression of osteoclast stimulating CSF2. In vitro studies on mouse osteoblasts showed impaired osteoblast mineralization upon tasquinimod treatment.
  
  
  CONCLUSIONS
  The present study shows that tasquinimod reduces establishment and progression of tumor growth in bone likely through a combination of effects on the pre-metastatic niche, homing, immunological status, and osteogenesis. It was concluded that tasquinimod interferes with the metastatic process, presumably by inhibition of tumor establishment. Hence, our data suggest that tasquinimod might be most effective in inhibiting the occurrence of new metastatic lesions.
authors.affiliation: Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lisa U
authors.initials: LU
authors.lastname: Magnusson
authors.affiliation: Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Hagberg Thulin
authors.affiliation: IPSEN Oncology and Biomarkers, Les Ulis, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Plas
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.affiliation: Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Damber
authors.affiliation: Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Welén
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000517:prevention & control / Q000556:secondary*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D064593:Heterografts; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007249:Inflammation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D015363:Quinolones; D013977:Tibia; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D011804:Quinolines; D015363:Quinolones; C516109:tasquinimod
keywords: bone microenvironment; immunosuppression; metastasis; pre-metastatic niche; prostate cancer; tasquinimod