Article ; Online: Cooperation among heterogeneous prostate cancer cells in the bone metastatic niche.
2016 Volume 36, Issue 20, Page(s) 2846–2856
Abstract: ... prostate cancer (PCa) cells expressing IL-1β. Interestingly, human mesenchymal stem cells exposed in vitro ... conditioned by IL-1β-expressing cancer cells served as a supportive niche also for coexisting IL-1β-lacking ... The growth of disseminated tumor cells into metastatic lesions depends on the establishment ...
| Abstract | The growth of disseminated tumor cells into metastatic lesions depends on the establishment of a favorable microenvironment in the stroma of the target organs. Here we show that mice treated with anakinra, an antagonist of the interleukin (IL)-1β receptor (IL-1R), or harboring a targeted deletion of IL-1R are significantly less prone to develop bone tumors when inoculated in the arterial circulation with human prostate cancer (PCa) cells expressing IL-1β. Interestingly, human mesenchymal stem cells exposed in vitro to medium conditioned by IL-1β-expressing cancer cells responded by upregulating S100A4, a marker of cancer-associated fibroblasts (CAFs), and this effect was blocked by anakinra. Analogously, the stroma adjacent to skeletal metastases generated in mice by IL-1β-expressing cancer cells showed a dramatic increase in S100A4, COX-2 and the alteration of 30 tumor-related genes as measured by Nanostring analysis. These effects were not observed in the stroma associated with the rare and much smaller metastases generated by the same cells in IL-1R knockout animals, confirming that tumor-secreted IL-1β generates skeletal CAFs and conditions the surrounding bone microenvironment. In skeletal lesions from patients with metastatic PCa, histological and molecular analyses revealed that IL-1β is highly expressed in cancer cells in which the androgen receptor (AR) is not detected (AR-), whereas this cytokine is uniformly absent in the AR-positive (AR+) metastatic cells. The stroma conditioned by IL-1β-expressing cancer cells served as a supportive niche also for coexisting IL-1β-lacking cancer cells, which are otherwise unable to generate tumors after independently seeding the skeleton of mice. This niche is established very early following tumor seeding and hints to a role of IL-1β in promoting early colonization of PCa at the skeletal level. |
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| MeSH term(s) | Animals ; Biomarkers ; Bone Neoplasms/metabolism ; Bone Neoplasms/secondary ; Cell Communication ; Cell Line, Tumor ; Cell Proliferation ; Disease Models, Animal ; Gene Expression ; Heterografts ; Humans ; Interleukin-1beta/metabolism ; Male ; Mesenchymal Stem Cells/metabolism ; Mice ; Neoplasm Metastasis ; Phenotype ; Prostatic Neoplasms/pathology ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Signal Transduction ; Stromal Cells/metabolism ; Tumor Microenvironment | |||||
| Chemical Substances | Biomarkers ; Interleukin-1beta ; Receptors, Androgen | |||||
| Language | English | |||||
| Publishing date | 2016-12-19 | |||||
| Publishing country | England | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 639046-8 | |||||
| ISSN | 1476-5594 ; 0950-9232 | |||||
| ISSN (online) | 1476-5594 | |||||
| ISSN | 0950-9232 | |||||
| DOI | 10.1038/onc.2016.436 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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