Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany.
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, The University of Cambridge, United Kingdom.
EBioMedicine. 2019 Oct;48:161-168. doi: 10.1016/j.ebiom.2019.09.024. Epub 2019 Oct 6.
Pancreatic ductal adenocarcinoma (PDAC) is characterised by extensive matrix deposition that has been implicated in impaired drug delivery and therapeutic resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates collagen deposition and is highly upregulated in the activated stroma subtype with poor prognosis in PDAC patients.
Kras;p48-Cre;SPARC (KC-SPARC) and Kras;p48-Cre;SPARC (KC-SPARC) were generated and analysed at different stages of carcinogenesis by histological grading, immunohistochemistry for epithelial and stromal markers, survival and preclinical analysis. Pharmacokinetic and pharmacodynamic studies were conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunohistochemistry following gemcitabine treatment (100 mg/kg) in vivo.
Global genetic ablation of SPARC in a Kras driven mouse model resulted in significantly reduced overall and mature collagen deposition around early and advanced pancreatic intraepithelial neoplasia (PanIN) lesions and in invasive PDAC (p < .001). However, detailed pathological scoring and molecular analysis showed no effects on PanIN to PDAC progression, vessel density (CD31), tumour incidence, grading or metastatic frequency. Despite comparable tumour kinetics, ablation of SPARC resulted in a significantly shortened survival in KC-SPARC mice (280 days versus 485 days, p < .03, log-rank-test). Using LC-MS/MS, we show that SPARC dependent collagen deposition does not affect intratumoural gemcitabine accumulation or immediate therapeutic response in tumour bearing KC-SPARC and KC-SPARCmice.
Global SPARC ablation reduces the collagen-rich microenvironment in murine PDAC. Moreover, global SPARC depletion did not affect tumour growth kinetics, grading or metastatic frequency. Notably, the dense-collagen matrix did not restrict access of gemcitabine to the tumour. These findings may have direct translational implications in clinical trial design.
胰腺导管腺癌（PDAC）的特征是广泛的基质沉积，这与药物输送受损和治疗耐药性有关。富含半胱氨酸的酸性分泌蛋白（SPARC）是一种基质细胞蛋白，可调节胶原蛋白的沉积，并在 PDAC 患者中预后不良的激活基质亚型中高度上调。
通过组织学分级、上皮和基质标志物的免疫组织化学、生存和临床前分析，生成并分析 Kras;p48-Cre;SPARC（KC-SPARC）和 Kras;p48-Cre;SPARC（KC-SPARC）在不同癌变阶段的情况。通过液相色谱-串联质谱（LC-MS/MS）和体内吉西他滨（100mg/kg）治疗后的免疫组织化学进行药代动力学和药效学研究。
在 Kras 驱动的小鼠模型中，SPARC 的全局遗传缺失导致早期和晚期胰腺上皮内瘤变（PanIN）病变和侵袭性 PDAC 周围的总胶原和成熟胶原沉积显著减少（p<.001）。然而，详细的病理评分和分子分析显示，PanIN 向 PDAC 进展、血管密度（CD31）、肿瘤发生率、分级或转移频率没有影响。尽管肿瘤动力学相似，但 KC-SPARC 小鼠中 SPARC 的缺失导致生存时间明显缩短（280 天对 485 天，p<.03，对数秩检验）。使用 LC-MS/MS，我们表明 SPARC 依赖性胶原蛋白沉积不会影响荷瘤 KC-SPARC 和 KC-SPARCmice 中的肿瘤内吉西他滨积累或即时治疗反应。
全球 SPARC 缺失可减少小鼠 PDAC 中的富含胶原蛋白的微环境。此外，全球 SPARC 耗竭不影响肿瘤生长动力学、分级或转移频率。值得注意的是，致密胶原基质并没有限制吉西他滨进入肿瘤。这些发现可能对临床试验设计具有直接的转化意义。
