Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer.
Jeremy J McGuireJeremy S FrielingChen Hao LoTao LiAyaz MuhammadHarshani R LawrenceNicholas J LawrenceLeah M CookConor C LynchPublished in: Nature communications (2021)
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.
Keyphrases
- prostate cancer
- mesenchymal stem cells
- induced apoptosis
- radical prostatectomy
- endoplasmic reticulum stress
- bone marrow
- cell proliferation
- oxidative stress
- umbilical cord
- bone mineral density
- cell cycle arrest
- small cell lung cancer
- squamous cell carcinoma
- signaling pathway
- soft tissue
- cell death
- stem cells
- small molecule
- postmenopausal women
- bone regeneration
- radiation therapy
- locally advanced
- free survival
- drug induced