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.
Nat Commun. 2021 Feb 1;12(1):723. doi: 10.1038/s41467-021-20962-6.
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.
骨转移前列腺癌 (PCa) 可促进间充质干细胞 (MSC) 的募集，并促使其分化为成骨细胞。然而，骨髓来源的 MSC 对 PCa 细胞的影响尚未得到充分探索。在这里，我们报告 MSC 衍生的白细胞介素-28 (IL-28) 通过 IL-28 受体 alpha (IL-28Rα)-STAT1 信号触发前列腺癌细胞凋亡。然而，慢性暴露于 MSC 会导致对 IL-28 诱导的细胞凋亡和多西紫杉醇等治疗药物产生耐药的前列腺癌细胞的选择。此外，MSC 选择/IL-28 耐药的前列腺癌细胞在骨内以更快的速度生长。对细胞凋亡的获得性耐药是 PCa 细胞内在的，并与通过 STAT1 向 STAT3 的 IL-28Rα 信号转导的转变有关。值得注意的是，STAT3 缺失或抑制会损害 MSC 选择的前列腺癌细胞的生长和存活。因此，骨髓 MSC 驱动了治疗耐药性骨转移前列腺癌的出现，但通过靶向 STAT3 可以阻止这种情况的发生。
