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Tasquinimod inhibits prostate cancer growth in bone through alterations in the bone microenvironment
The Prostate, 2016-03, Vol.76 (4), p.383-393
Magnusson, Lisa U.
Hagberg Thulin, Malin
Plas, Pascale
Olsson, Anders
Damber, Jan-Erik
Welén, Karin
2016
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Magnusson, Lisa U.
Hagberg Thulin, Malin
Plas, Pascale
Olsson, Anders
Damber, Jan-Erik
Welén, Karin
Titel
Tasquinimod inhibits prostate cancer growth in bone through alterations in the bone microenvironment
Ist Teil von
The Prostate, 2016-03, Vol.76 (4), p.383-393
Ort / Verlag
United States: Blackwell Publishing Ltd
Erscheinungsjahr
2016
Quelle
MEDLINE
Beschreibungen/Notizen
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. Prostate 76:383–393, 2016. © 2015 Wiley Periodicals, Inc.
Sprache
Englisch
Identifikatoren
ISSN: 0270-4137, 1097-0045
eISSN: 1097-0045
DOI: 10.1002/pros.23133
Titel-ID: cdi_swepub_primary_oai_gup_ub_gu_se_228711
Format
–
Schlagworte
Animals
,
Antineoplastic Agents
,
bone microenvironment
,
Bone Neoplasms - drug therapy
,
Bone Neoplasms - prevention & control
,
Bone Neoplasms - secondary
,
Cell Line, Tumor
,
Cytokines - blood
,
Heterografts
,
Humans
,
Immune Tolerance - drug effects
,
immunosuppression
,
Inflammation
,
Male
,
metastasis
,
Mice
,
Mice, Inbred BALB C
,
Mice, Nude
,
Neoplasm Metastasis - prevention & control
,
Osteoblasts - drug effects
,
Osteogenesis - drug effects
,
pre-metastatic niche
,
prostate cancer
,
Prostatic Neoplasms - drug therapy
,
Prostatic Neoplasms - pathology
,
Prostatic Neoplasms, Castration-Resistant - drug therapy
,
Prostatic Neoplasms, Castration-Resistant - pathology
,
Quinolines - pharmacology
,
Quinolines - therapeutic use
,
Quinolones
,
tasquinimod
,
Tibia
,
Tumor Microenvironment - drug effects
,
Urologi och njurmedicin
,
Urology and Nephrology
,
Xenograft Model Antitumor Assays
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