Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells
Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells
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DOI：
10.1038/cdd.2014.97
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发表时间：
2015-06-01
影响因子：
12.4
通讯作者：
Hodny, Z.
中科院分区：
文献类型：
--
作者：
Kyjacova, L.;Hubackova, S.;Hodny, Z.
分段电离辐射结合手术或激素治疗是中高危局限性前列腺癌的首选治疗方法。前列腺癌放疗失败的主要原因之一是放射抗性和存活细胞的进一步扩散。在这项研究中，将四种转移源性人类前列腺癌细胞系（DU145、PC-3、LNCaP 和 22RV1）暴露于临床相关每日剂量的电离辐射（35 剂 2 Gy）中，导致产生两个辐射存活群体：表达常见衰老相关标记的贴壁衰老样细胞和具有活跃 Notch 信号传导和干细胞标记表达的非贴壁抗失巢凋亡干细胞样细胞CD133、Oct-4、Sox2 和 Nanog。虽然在辐射治疗结束后不久，一部分存活下来的贴壁细胞恢复增殖，但非贴壁细胞仅在辐射引起的粘附丧失几周后重新贴壁时才开始增殖。与未受辐射的亲代细胞一样，辐射后存活的重新贴壁 DU145 细胞在免疫功能低下的小鼠中具有致瘤性。辐射诱导的粘附丧失取决于 Snail 的表达，因为 siRNA/shRNA 介导的 Snail 敲低可防止细胞脱离。另一方面，非贴壁细胞的存活需要活跃的 Erk 信号传导，因为 MEK 选择性抑制剂对 Erk1/2 的化学抑制或 Erk1/2 敲低会导致非贴壁细胞部分中失巢凋亡介导的死亡。值得注意的是，虽然 Erk 和 PI3K-Akt 信号传导的联合抑制引发了非贴壁细胞部分的细胞死亡，并阻止了前列腺癌细胞贴壁群体的增殖，但这种联合治疗对对照正常人二倍体细胞的生长影响甚微（如果有的话）。这些结果有助于更好地理解辐射引起的应激反应和人类转移性前列腺癌细胞的异质性，记录治疗引起的可塑性和表型不同的细胞亚群，并提出利用它们对放射增敏药物的不同敏感性来克服放射抗性的方法。
Fractionated ionizing radiation combined with surgery or hormone therapy represents the first-choice treatment for medium to high-risk localized prostate carcinoma. One of the main reasons for the failure of radiotherapy in prostate cancer is radioresistance and further dissemination of surviving cells. In this study, exposure of four metastasis-derived human prostate cancer cell lines (DU145, PC-3, LNCaP and 22RV1) to clinically relevant daily fractions of ionizing radiation (35 doses of 2 Gy) resulted in generation of two radiation-surviving populations: adherent senescent-like cells expressing common senescence-associated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2 and Nanog. While a subset of the radiation-surviving adherent cells resumed proliferation shortly after completion of the irradiation regimen, the non-adherent cells started to proliferate only on their reattachment several weeks after the radiation-induced loss of adhesion. Like the parental non-irradiated cells, radiation-surviving re-adherent DU145 cells were tumorigenic in immunocompromised mice. The radiation-induced loss of adhesion was dependent on expression of Snail, as siRNA/shRNA-mediated knockdown of Snail prevented cell detachment. On the other hand, survival of the non-adherent cells required active Erk signaling, as chemical inhibition of Erk1/2 by a MEK-selective inhibitor or Erk1/2 knockdown resulted in anoikis-mediated death in the non-adherent cell fraction. Notably, whereas combined inhibition of Erk and PI3K-Akt signaling triggered cell death in the non-adherent cell fraction and blocked proliferation of the adherent population of the prostate cancer cells, such combined treatment had only marginal if any impact on growth of control normal human diploid cells. These results contribute to better understanding of radiation-induced stress response and heterogeneity of human metastatic prostate cancer cells, document treatment-induced plasticity and phenotypically distinct cell subsets, and suggest the way to exploit their differential sensitivity to radiosensitizing drugs in overcoming radioresistance.