| Autor: |
McGuire JJ; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA.; Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Frieling JS; Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Lo CH; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA.; Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Li T; Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Muhammad A; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Lawrence HR; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Lawrence NJ; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Cook LM; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA., Lynch CC; Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. conor.lynch@moffitt.org. |
| Abstrakt: |
Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3. |
