PO.TB04.06 · 肿瘤生物学
患者来源原位异种移植模型预测胰腺导管腺癌的化疗应答：转化研究的新兴平台
Patient-derived orthotopic xenograft models predict chemotherapeutic response in pancreatic ductal adenocarcinoma: an emerging platform for translational research
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摘要 Abstract
中文摘要
背景：胰腺导管腺癌（PDAC）是癌症死亡的第三大原因。目前的化疗方案以吉西他滨（gemcitabine）为骨架。然而，化疗应答率和预后仍然很差，五年生存率仅为13%。模拟肿瘤微环境的动物模型已被用于临床前和治疗研究，但皮下异种移植模型无法重现临床发生部位和人PDAC的化疗应答。在本研究中，我们使用了患者来源原位异种移植（PDOX）小鼠模型，其肿瘤定位于胰腺，能够模拟自然的肿瘤微环境，以检测化疗药物吉西他滨对PDAC进展的疗效，并将其与患者的临床应答进行比较。
方法：共有71例PDAC患者签署知情同意书，经病理学家审查后采集其肿瘤/血液标本。将一例代表性的部分/中度化疗应答PDAC患者（PaCa23）和一例代表性的化疗应答不良PDAC患者（PaCa54）的肿瘤细胞进行扩增、分离，并注射到NOD/SCID小鼠的胰腺内。吉西他滨（100 mg/kg）每周经静脉输注给药一次，持续4周。每周监测肿瘤体积和小鼠体重。小鼠安乐死后，采集肿瘤进行肿瘤重量测量。进行苏木精-伊红染色和OpalTM四色免疫荧光染色，用于肿瘤细胞谱和肿瘤微环境研究。
结果：我们在PaCa23和PaCa54中的PDOX模型均保留了其供体肿瘤的主要组织学特征，具有相似的基质细胞浸润模式，并在传代过程中保持稳定。吉西他滨组未观察到显著的体重下降。与对照组相比，PaCa23肿瘤对吉西他滨有应答，肿瘤体积和肿瘤重量显著减少（分别为p=0.007和p=0.01）。PaCa54肿瘤对吉西他滨应答不佳，与对照组相比肿瘤重量无显著下降（p>0.05）。
结论：我们的PDOX小鼠模型成功重现了人PDAC的关键组织病理学和微环境特征，并反映了患者特异性的吉西他滨治疗应答。在PaCa23和PaCa54模型中观察到的不同肿瘤应答与其各自的临床结局相符，突显了该平台的预测价值。这一原位模型作为评估化疗疗效、指导个体化治疗策略以及在临床相关微环境中研究肿瘤生物学的临床前工具，具有重大前景。
查看英文原文 English abstract
Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer death. Current chemotherapy options are centered on a gemcitabine as backbone. However, the chemotherapy responsive rate and prognosis are still very poor with a five-year survival rate of 13%. Animal models mimicking tumor microenvironment have been used for pre-clinical and therapeutic studies, but the subcutaneous xenograft model does not replicate the clinical location and human PDAC chemotherapy responses. In this study, we used patient-derived orthotopic xenograft (PDOX) mouse models, with tumors localized to the pancreases, that mimic the natural tumor microenvironment, to test the efficacy of chemotherapeutic gemcitabine on PDAC progression and compare to their clinical response.
Methods: Totally 71 PDAC patients were consented and their tumor/blood specimens were collected after reviewed by pathologists. Tumor cells from one representative partial/moderate chemo-responding PDAC patients (PaCa23) and one representative poor chemo-responding PDAC patient (PaCa54), were expanded, isolated and intra-pancreas injected to NOD/SCID mice. Gemcitabine (100 mg/kg) was administered weekly by intravenous infusion for 4 weeks. Tumor volumes and mouse body weights were monitored weekly. After mice were euthanized, tumors were collected for tumor weight measurement. Hematoxylin & Eosin staining and OpalTM 4-color immunofluorescence staining were performed for tumor cell profile and tumor microenvironment study.
Results: Our PDOX model in both PaCa23 and PaCa54 retains the principal histologic characteristics of their donor tumor with similar infiltration patterns of stromal cells and remains stable across passages. No significant body weight loss was observed in the gemcitabine group. PaCa23 tumor responded to gemcitabine with significantly decreased tumor volume and tumor weight compared to control group (p=0.007 and p=0.01, respectively). PaCa54 tumor poorly responded to gemcitabine without significant tumor weight decrease compared to controls (p>0.05).
Conclusion: Our PDOX mouse model successfully recapitulates key histopathological and microenvironmental features of human PDAC and reflects patient-specific responses to gemcitabine treatment. The differential tumor response observed in PaCa23 and PaCa54 models mirrors their respective clinical outcomes, underscoring the predictive value of this platform. This orthotopic model holds significant promise as a preclinical tool for evaluating chemotherapeutic efficacy, guiding personalized therapy strategies, and studying tumor biology within a clinically relevant microenvironment.
利益披露 Disclosure
X. Zhang, None..
N. Bolton, None..
A. Ray, None..
G. Maresh, None..
R. Graham, None..
L. Li, None.