Juric Vladislava, Ruffell Brian, Evason Kimberley J, Hu Junjie, Che Li, Wang Linlin, Chen Xin, Bishop J Michael
GW Hooper Research Foundation, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
J Hepatol. 2016 Apr;64(4):881-90. doi: 10.1016/j.jhep.2015.11.025. Epub 2015 Nov 27.
BACKGROUND & AIMS: The leukocyte composition of tumors is heterogeneous, as is the involvement of each leukocyte subset in promoting or restraining tumorigenesis. This heterogeneity reflects the tissue of origin, tumor stage, and the functional state of leukocyte activation, but its biological roots remain poorly understood. Since tumorigenesis is driven by various genetic events, we assessed the role of driver genes in shaping the profiles and the roles of leukocytes in tumorigenesis.
Mouse liver tumors were induced by hepatic overexpression of either MYC or the combination of myristoylated AKT and NRAS(V12) oncogenes via hydrodynamic transfection. A comparative, flow cytometry- and histology-based immunophenotyping of liver-infiltrating leukocytes was performed at various stages of liver tumorigenesis. The roles of the most abundant leukocyte subsets in tumorigenesis were addressed by immunodepletion. The contribution of liver injury was assessed by comparing the injury-inducing hydrodynamic transfection model to a model in which MYC is an inducible transgene.
Myristoylated AKT and NRAS(V12) promoted a marked recruitment of CD11b(+)Ly6G(hi)Ly6C(int) neutrophils and CD11b(+)Ly6G(-)Ly6C(hi) monocytes to the liver, but their immunodepletion did not alter tumorigenesis. In contrast, despite minimal invasion by monocytes/neutrophils during MYC-driven tumorigenesis, immunodepletion of these cells reduced MYC tumor burden and extended survival. MYC-driven tumor initiation was augmented specifically by Ly6C+ monocytes and their ability to promote liver injury.
Our results demonstrate that leukocyte profiles do not necessarily predict their involvement in tumorigenesis, the functional role of leukocytes can be shaped by oncogenes, and that monocyte-dependent tissue injury selectively cooperates with MYC during tumorigenesis.
肿瘤中的白细胞组成具有异质性，每个白细胞亚群在促进或抑制肿瘤发生中的作用也是如此。这种异质性反映了肿瘤的起源组织、肿瘤分期以及白细胞激活的功能状态，但其生物学根源仍知之甚少。由于肿瘤发生是由各种基因事件驱动的，我们评估了驱动基因在塑造白细胞谱以及白细胞在肿瘤发生中的作用方面的作用。
通过流体动力学转染，在肝脏中过表达MYC或肉豆蔻酰化的AKT与NRAS(V12)癌基因的组合来诱导小鼠肝肿瘤。在肝肿瘤发生的各个阶段，基于流式细胞术和组织学对肝脏浸润白细胞进行了比较性免疫表型分析。通过免疫清除法研究了肿瘤发生过程中最丰富的白细胞亚群的作用。通过将诱导损伤的流体动力学转染模型与MYC为可诱导转基因的模型进行比较，评估了肝损伤的作用。
肉豆蔻酰化的AKT和NRAS(V12)促进了CD11b(+)Ly6G(hi)Ly6C(int)中性粒细胞和CD11b(+)Ly6G(-)Ly6C(hi)单核细胞向肝脏的显著募集，但对它们的免疫清除并未改变肿瘤发生。相反，尽管在MYC驱动的肿瘤发生过程中单核细胞/中性粒细胞的浸润极少，但对这些细胞的免疫清除降低了MYC肿瘤负荷并延长了生存期。Ly6C+单核细胞及其促进肝损伤的能力特异性地增强了MYC驱动的肿瘤起始。
我们的结果表明，白细胞谱不一定能预测它们在肿瘤发生中的参与情况，白细胞的功能作用可由癌基因塑造，并且在肿瘤发生过程中，单核细胞依赖性组织损伤与MYC选择性协同作用。
