PO.EN01.02 · 内分泌肿瘤
肿瘤来源的 PTHrP-钙轴驱动心脏功能障碍,将癌症恶病质与死亡联系起来
A tumor-derived PTHrP-calcium axis drives cardiac dysfunction to connect cancer cachexia with mortality
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症恶病质(CC)对癌症相关死亡有重要影响,然而 CC 导致死亡的机制仍不明确。我们研究了心脏功能障碍是否是 CC 相关死亡的驱动因素。在 CC 的 C26 模型中,我们在疾病进展过程中使用连续心电遥测和超声心动图,全面评估了恶病质对心脏功能电学和机械成分的影响。恶病质的发生与平均每搏输出量显著降低(基线 30 μL 对比恶病质 13 μL,p = 0.001)和心输出量显著降低(基线 18 mL/min 对比恶病质 8 mL/min,p = 0.02)相关,终点时心肌萎缩显著增加(基线 145 mg 对比恶病质 110 mg,p < 0.0001)。死亡之前出现进行性传导异常,包括一度和二度房室传导阻滞、缓慢性心律失常和心房颤动。恶病质的发作与平均 QTc 时限显著缩短(基线 55 ms 对比恶病质 40 ms,p = 0.002)相关,这与显著的高钙血症(基线 8 mg/dL 对比恶病质 15 mg/dL,p < 0.0001)和低磷血症(基线 6.5 mg/dL 对比恶病质 4.5 mg/dL,p = 0.0044)相关。作为钙稳态紊乱的解释,我们在 C26 癌细胞中鉴定出甲状旁腺激素相关蛋白(PTHrP)的 RNA 和蛋白表达。为研究高钙血症是否是恶病质相关心脏功能障碍的驱动因素,我们通过持续输注唑来膦酸(ZA)对钙水平进行药物抑制。ZA 输注显著降低了平均血浆钙(p = 0.05),延迟了恶病质的发作(p = 0.03),并部分保留了每搏输出量和心输出量。我们假设,如果高钙血症依赖于 PTHrP,那么在 C26 细胞系中进行同基因 PTHrP 敲除将消除恶病质。荷 PTHrP-KO 肿瘤的小鼠保持非恶病质状态,尽管肿瘤大小与对照(scramble)相当,但电学功能(平均 QTc:scramble 40 ms 对比 KO 55 ms,p = 0.01)和机械功能(平均心输出量:scramble 8 mL/min 对比 KO 16 mL/min,p = 0.03)得以保留。综上所述,这些临床前数据表明,肿瘤来源的 PTHrP 在驱动 C26 模型的恶病质及相关心脏功能障碍中发挥主要作用,且心脏功能障碍可能是 CC 死亡的最终共同通路。我们的研究结果提出,PTHrP 驱动的恶病质可能是一个在生物学上独特且具有治疗相关性的癌症恶病质亚组。
查看英文原文 English abstract
Cancer cachexia (CC) contributes significantly to cancer-associated mortality, yet the mechanisms leading to death in CC remain poorly defined. We investigated whether cardiac dysfunction is a driver of CC-associated mortality. Using continuous ECG telemetry and echocardiography during disease progression in the C26 model of CC, we comprehensively assessed the effect of cachexia on electrical and mechanical components of cardiac function. The development of cachexia was associated with significantly reduced mean stroke volume (baseline 30 μL vs. cachectic 13 μL, p = 0.001) and cardiac output (baseline 18 mL/min vs. cachectic 8 mL/min, p = 0.02), with significantly increased cardiac muscle atrophy at endpoint (baseline 145 mg vs. cachectic 110 mg, p < 0.0001). Mortality was preceded by progressive conduction abnormalities, including first- and second-degree atrioventricular block, bradyarrhythmias, and atrial fibrillation. The onset of cachexia was associated with significantly reduced mean QTc duration (baseline 55 ms vs. cachectic 40 ms, p = 0.002), which correlated with marked hypercalcemia (baseline 8 mg/dL vs. cachectic 15 mg/dL, p < 0.0001) and hypophosphatemia (baseline 6.5 mg/dL vs. cachectic 4.5 mg/dL, p = 0.0044). As an explanation for perturbed calcium homeostasis, we identified RNA and protein expression of parathyroid hormone-related protein (PTHrP) in C26 cancer cells. To investigate whether hypercalcemia was a driver of cachexia-associated cardiac dysfunction, we pharmacologically suppressed calcium levels with continuously infused zoledronic acid (ZA). ZA infusion significantly lowered mean plasma calcium (p = 0.05), delayed the onset of cachexia (p = 0.03), and partially preserved stroke volume and cardiac output. We hypothesized that if hypercalcemia is PTHrP-dependent, then isogenic PTHrP knockout in the C26 cell line would obviate cachexia. Mice bearing PTHrP-KO tumors remained non-cachectic with preserved electrical function (mean QTc: scramble 40 ms vs. KO 55 ms, p = 0.01) and preserved mechanical function (mean cardiac output: scramble 8 mL/min vs. KO 16 mL/min, p = 0.03) despite comparable tumor size to scramble controls. Taken together, these preclinical data demonstrate that tumor-derived PTHrP plays a major role in driving cachexia and associated cardiac dysfunction in the C26 model, and that cardiac dysfunction may be a final common pathway of mortality in CC. Our findings raise the possibility that PTHrP-driven cachexia may be a biologically distinct and therapeutically relevant subgroup of cancer cachexia.
利益披露 Disclosure
T. M. Thakir, None..
M. Ferrer González, None.