Stafman Laura L, Williams Adele P, Garner Evan F, Aye Jamie M, Stewart Jerry E, Yoon Karina J, Whelan Kimberly, Beierle Elizabeth A
Department of Surgery, University of Alabama at Birmingham, Birmingham, AL.
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
Transl Oncol. 2019 Feb;12(2):200-208. doi: 10.1016/j.tranon.2018.10.008. Epub 2018 Nov 6.
Hepatoblastoma is the most common primary liver tumor in children, but treatment has not changed significantly in the past 20 years. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia (PIM) kinases promote tumorigenesis in hepatoblastoma. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to be responsible for chemoresistance, metastasis, relapse, and recurrence. The aim of this study was to identify SCLCCs in hepatoblastoma and determine the role of PIM kinases in SCLCCs. Hepatoblastoma cells were separated into CD133-enriched and CD133-depleted populations and the frequency of SCLCCs was assessed. CD133 expression was determined in the presence or absence of the PIM inhibitor, AZD1208. The effects of AZD1208 on proliferation, apoptosis, and motility were assessed in vitro and the effect of AZD1208 on tumor growth was examined in vivo. We identified CD133 as a marker for SCLCCs in hepatoblastoma and showed that PIM kinases promote a SCLCC phenotype. PIM kinase inhibition with AZD1208 decreased proliferation, migration, and invasion and increased apoptosis in both SCLCCs and non-SCLCCs in a long-term passaged hepatoblastoma cell line and patient-derived xenograft. Additionally, tumor growth in mice implanted with hepatoblastoma SCLCCs was decreased with PIM inhibition such that 57% of the tumors regressed. These findings identify CD133 as a marker for SCLCCs in hepatoblastoma and provide evidence that inhibition of PIM kinases decreases stemness and tumorigenicity of SCLCCs in hepatoblastoma, making them potential therapeutic targets for the treatment of hepatoblastoma.
肝母细胞瘤是儿童最常见的原发性肝脏肿瘤，但在过去20年中治疗方法并没有显著改变。我们之前已经证明，莫洛尼鼠白血病病毒（Moloney murine leukemia virus）前病毒整合位点（Proviral Integration site，PIM）激酶促进肝母细胞瘤的肿瘤发生。干细胞样癌细胞（Stem cell-like cancer cells，SCLCCs）是一类被认为与化疗耐药、转移、复发和再发有关的细胞亚群。本研究的目的是在肝母细胞瘤中鉴定SCLCCs，并确定PIM激酶在SCLCCs中的作用。将肝母细胞瘤细胞分为富含CD133和缺乏CD133的群体，并评估SCLCCs的频率。在有或没有PIM抑制剂AZD1208的情况下测定CD133的表达。在体外评估AZD1208对增殖、凋亡和运动性的影响，并在体内检查AZD1208对肿瘤生长的影响。我们将CD133鉴定为肝母细胞瘤中SCLCCs的标志物，并表明PIM激酶促进SCLCCs表型。用AZD1208抑制PIM激酶可降低长期传代的肝母细胞瘤细胞系和患者来源异种移植瘤中SCLCCs和非SCLCCs的增殖、迁移和侵袭，并增加凋亡。此外，PIM抑制可降低植入肝母细胞瘤SCLCCs的小鼠的肿瘤生长，使57%的肿瘤消退。这些发现将CD133鉴定为肝母细胞瘤中SCLCCs的标志物，并提供证据表明抑制PIM激酶可降低肝母细胞瘤中SCLCCs的干性和致瘤性，使其成为治疗肝母细胞瘤的潜在治疗靶点。
