PO.CL11.01 · 临床研究
胰腺腺癌癌-基质相互作用对心脏结构和功能的作用
The role of pancreatic adenocarcinoma cancer-stromal interactions on cardiac structure and function
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
尽管治疗有所进步，胰腺导管腺癌（PDAC）的5年生存率仍低至<13%。PDAC患者的心脏特异性中位生存也显著低于其他消化道癌症患者。虽然癌症恶病质通过骨骼肌丢失影响生存，但心脏功能对PDAC结局的贡献尚不清楚。我们旨在利用最具代表性的人类临床前模型评估心脏组织结构和功能。这将为PDAC相关的心脏重构及其可能改善总生存的干预措施的临床意义提供见解。我们将一株PDAC患者来源异种移植物（PDX）以异位方式植入五只NSG小鼠、以原位方式植入五只NSG小鼠，另有五只NSG小鼠接受假手术作为对照。每周监测肿瘤体积，一旦达到1.5cm，即进行超声心动图和Millar导管检查，以评估三组之间的心脏结构和功能。采集心肌、腓肠肌和肿瘤进行组织学和分子分析，包括用于结构评估的染色以及用于评估与肿瘤负荷相关变化的RNA测序（正在进行中）。采用ANOVA和简单非配对t检验，显著性值设定为p<0.05。超声心动图测量的整体纵向应变（GLS）在各组中均在正常值范围内（-18至-25%），假手术组（−20.3%）、异位组（−21.2%）和原位组（−19.9%）的均值之间无显著差异。然而，存在一个轻微趋势，即原位组的GLS相比对照组有所下降。压力-容积环（PV Loop）数据显示，异位组（0.86）和原位组（1.06）的左心室顺应性（EDPVR）均值相比对照组（0.22）下降。原位组EDPVR均值与对照组均值存在统计学差异，简单非配对t检验p值为0.02。原位组相比对照组观察到的GLS轻微降低，可能提示荷PDAC小鼠存在早期收缩功能损害。此外，结果提示肿瘤负荷与EDPVR受损相关，原位组显示出更明显的僵硬，表现为与对照组相比EDPVR显著升高。这可能提示在肿瘤相关心脏重构背景下的早期舒张功能障碍。我们还预期荷PDAC小鼠将表现出心脏组织重构，其特征为组织学改变和转录改变，将心脏功能下降与癌症进展联系起来。识别PDAC患者的早期心脏改变将有助于确定可能最终改善治疗耐受性和临床结局的干预措施。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival of <13% despite advances in therapy. Patients with PDAC also experience significantly lower cardiac-specific median survival compared to those with other GI cancers. While cancer cachexia impacts survival through skeletal muscle loss, the contribution of cardiac function to outcomes in PDAC is unknown. We aim to evaluate cardiac tissue structure and function in the most representative human preclinical model. This will provide insight into cardiac remodeling associated with PDAC and its clinical implication for possible interventions to improve overall survival. We implanted a PDAC patient-derived xenograft (PDX) into five NSG mice heterotopically and five NSG mice orthotopically, with five NSG mice receiving sham surgeries as controls. Tumor volumes were monitored weekly and once reaching 1.5cm, echocardiography and Millar catheterization were performed to assess cardiac structure and function between the three groups. Cardiac muscle, gastrocnemius muscle and tumors were collected for histologic and molecular analysis, including staining for structural assessment RNA sequencing to assess for changes associated with tumor burden, which is ongoing. An ANOVA and simple unpaired t-test were used with a significance value set at p < 0.05.Global longitudinal strain (GLS) measured by echocardiogram was within the normal values (-18 to -25%) across the groups, with no significant difference between the means of the sham (−20.3%), heterotopic (−21.2%), and orthotopic (−19.9%) groups. However, there is a slight trend showing a decline in GLS in the orthotopic group compared to the control group. The PV Loop data show a decline in left ventricular compliance (EDPVR) means in the heterotopic group (0.86) and orthotopic group (1.06) compared to the control group (0.22). The orthotopic group EDPVR mean is statistically different from the control group mean, with a simple unpaired t-test p-value of 0.02. The slight reduction in GLS observed in the orthotopic group relative to controls may indicate the presence of early systolic impairment in PDAC-bearing mice. Additionally, the results suggest that tumor burden is associated with impaired EDPVR, with the orthotopic group showing more stiffening as evidenced by a significantly elevated EDPVR when compared to the control group. This may indicate early diastolic dysfunction in the context of tumor related cardiac remodeling. We also anticipate that PDAC bearing mice will exhibit cardiac tissue remodeling, characterized by histological changes and transcriptional alterations linking cardiac decline and cancer progression. Recognizing early cardiac changes in patients with PDAC will help identify interventions that may ultimately improve treatment tolerance and clinical outcomes.
利益披露 Disclosure
A. E. Gibson, None..
E. Mezzaroma, None.