The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.
- MeSH
- apoptóza účinky léků MeSH
- bortezomib farmakologie MeSH
- chemokin CCL27 metabolismus MeSH
- chemorezistence * MeSH
- inhibitory proteasomu farmakologie MeSH
- interakce mezi receptory a ligandy účinky léků MeSH
- interleukin-10 genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie enzymologie genetika patologie MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí MeSH
- pohyb buněk účinky léků MeSH
- proliferace buněk účinky léků MeSH
- proteasomový endopeptidasový komplex metabolismus MeSH
- receptory CCR10 genetika metabolismus MeSH
- receptory interleukinu-10 genetika metabolismus MeSH
- RNA interference MeSH
- senioři MeSH
- signální transdukce účinky léků MeSH
- transfekce MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
