Department of General, Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany.
Berlin School of Integrative Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
J Cachexia Sarcopenia Muscle. 2019 Oct;10(5):1128-1142. doi: 10.1002/jcsm.12450. Epub 2019 Jul 18.
Cancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia; however, clinical studies with anti-inflammatory drugs failed to show distinct cachexia-inhibiting effects. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)-associated cachexia.
A transgenic HCC mouse model was intercrossed with mice harbouring a defect in myeloid cell-mediated inflammation. Body composition of mice was analysed via nuclear magnetic resonance spectroscopy and microcomputed tomography. Quantitative PCR was used to determine adipose tissue browning and polarization of adipose tissue macrophages. The activation state of distinct areas of the hypothalamus was analysed via immunofluorescence. Multispectral immunofluorescence imaging and immunoblot were applied to characterize sympathetic neurons and macrophages in visceral adipose tissue. Quantification of pro-inflammatory cytokines in mouse serum was performed with a multiplex immunoassay. Visceral adipose tissue of HCC patients was quantified via the L3 index of computed tomography scans obtained during routine clinical care.
We identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography-based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell-mediated inflammation defect resulted in reduced expression of pro-inflammatory cytokines in the serum of HCC-bearing mice, this unexpectedly did not translate into diminished but rather enhanced cachexia-associated fat loss. Defective myeloid cell-mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer-induced fat loss.
Myeloid cell-mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer-induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti-inflammatory drugs.
癌症恶病质是医学肿瘤学的一个主要障碍，因为它与治疗反应不良和总生存时间降低有关。全身性炎症被认为是癌症恶病质的关键驱动因素；然而，抗炎症药物的临床研究未能显示出明显的抑制恶病质的作用。为了解决这一矛盾，我们研究了固有免疫细胞对肝癌（HCC）相关恶病质的功能重要性。
将转基因 HCC 小鼠模型与骨髓细胞介导的炎症缺陷小鼠进行杂交。通过磁共振波谱和微计算机断层扫描分析小鼠的身体成分。定量 PCR 用于确定脂肪组织褐变和脂肪组织巨噬细胞的极化。通过免疫荧光分析不同下丘脑区域的激活状态。应用多光谱免疫荧光成像和免疫印迹来描述内脏脂肪组织中的交感神经元和巨噬细胞。通过多重免疫测定法测定小鼠血清中的促炎细胞因子。通过在常规临床护理中获得的计算机断层扫描（CT）扫描的 L3 指数来量化 HCC 患者的内脏脂肪组织。
我们在 HCC 小鼠模型中发现了明显的恶病质，表现为内脏脂肪和瘦肉量的显著减少。基于 CT 的分析表明，一部分 HCC 患者表现出内脏脂肪减少，补充了小鼠数据。虽然骨髓细胞介导的炎症缺陷导致 HCC 小鼠血清中促炎细胞因子的表达减少，但这并没有转化为减少，而是增强了与恶病质相关的脂肪丢失。骨髓细胞介导的炎症缺陷与内脏脂肪组织中巨噬细胞丰度降低有关，这表明局部巨噬细胞在调节癌症引起的脂肪损失中起作用。
骨髓细胞介导的炎症在 HCC 小鼠模型中表现出一种相当意外的有益作用。这些结果表明，免疫细胞能够保护宿主免受癌症引起的组织消耗，为恶病质的发病机制增加了一层复杂性，并为抗炎症药物的临床研究的矛盾结果提供了潜在的解释。
