Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer
Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer
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DOI：
10.3390/cells9010058
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发表时间：
2020-01-01
期刊：
影响因子：
6
通讯作者：
Neesse, Albrecht
中科院分区：
文献类型：
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作者：
Hasselluhn, Marie C.;Klein, Lukas;Neesse, Albrecht
Kras(G12D/+)、LSL-Trp53(R172H/+)、PDX-1-Cre(KPC)小鼠模型经常用于临床前治疗试验，特别是抗间质治疗。在这里，我们调查可能指导临床前试验设计的组织病理学特征对预后的影响。应用免疫组织化学和免疫荧光技术对46只KPC小鼠胰腺癌组织的增殖指数(Ki67)、有丝分裂指数(PhH3)、细胞凋亡率(CC3)、胶原含量、酸性富含半胱氨酸的分泌蛋白(SPARC)、透明质酸(HA)和α-平滑肌肌动蛋白(α-SMA)进行了定量分析。检测平均血管密度(MVD)、平均管腔面积(MLA)、分级、活化间质指数(ASI)和成纤维细胞增殖率(α-SMA/Ki67)。使用Kaplan-Meier估计器和COX回归模型对连续变量进行的单变量分析没有显示生存率与任何分析参数之间的关联。Spearman相关分析显示结缔组织增生与分化程度呈负相关(Rho=-0.84)。Ki67和PHH3作为增殖标记物协同作用(Rho=0.54)，而SPARC表达与HA含量呈正相关(Rho=0.37)。MVD与MLA呈正相关(Rho=0.31)，而MLA与CC3呈正相关(Rho=0.45)。此外，MVD增加与成纤维细胞增殖率增加相关(α-SMA+Ki67；Rho=0.36)。我们的初步研究提供了证据，证明KPC小鼠原发肿瘤的个别组织病理学参数与生存无关，并可能暗示全身肿瘤相关效应的重要性，如恶病质。
The Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and alpha-smooth muscle actin (alpha-SMA). Furthermore, mean vessel density (MVD), mean lumen area (MLA), grading, activated stroma index (ASI), and fibroblast-proliferation rate (alpha-SMA/Ki67) were assessed. Univariate analysis using the Kaplan-Meier estimator and Cox regression model for continuous variables did not show association between survival and any of the analyzed parameters. Spearman correlation demonstrated that desmoplasia was inversely correlated with differentiated tumor grade (rho = -0.84). Ki67 and PHH3 synergized as proliferation markers (rho = 0.54), while SPARC expression was positively correlated with HA content (rho = 0.37). MVD and MLA were correlated with each other (rho = 0.31), while MLA positively correlated with CC3 (rho = 0.45). Additionally, increased MVD was correlated with increased fibroblast proliferation rate (alpha-SMA + Ki67; rho = 0.36). Our pilot study provides evidence that individual histopathological parameters of the primary tumor of KPC mice are not associated with survival, and may hint at the importance of systemic tumor-related effects such as cachexia.