The Role of Fibroblasts in Pancreatic Cancer: Extracellular Matrix Versus Paracrine Factors.
The Role of Fibroblasts in Pancreatic Cancer: Extracellular Matrix Versus Paracrine Factors.
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DOI：
10.1016/j.tranon.2017.04.009
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发表时间：
2017-08
影响因子：
5
通讯作者：
Wellner UF
中科院分区：
文献类型：
--
作者：
Bolm L;Cigolla S;Wittel UA;Hopt UT;Keck T;Rades D;Bronsert P;Wellner UF
背景与目的：促结缔组织增生症是胰腺导管腺癌的一个特征，也是一种可疑的肿瘤进展机制。间质的主要成分包括癌症相关成纤维细胞(CAF)和细胞外基质(ECM)。这项研究的目的是在体外环境和大规模临床队列研究中剖析CAF、ECM和PDAC细胞之间的相互作用。方法和材料：接受PDAC手术的患者来自我们前瞻性维护的临床数据库。对胰腺十二指肠切除标本应用标准病理学方案，也评估CAF活性为CAF 0级或CAF+级。在条件培养液实验装置中，评价了一系列胰腺癌细胞(PCCs)与小鼠胚胎成纤维细胞(NIH3T3)之间的相互作用。结果：2001-2011年间共收治111例PDAC患者。单变量分析显示CAF分级+(P=.030)、阳性M状态(P<；.001)和淋巴结比(LNR)>；0.1(P=.045)影响总体生存率。独立预后因素为CAF分级(P=.050)和阳性M状态(P=.002)。CAF分级与N状态(CC=0.206，P=.030)、LNR(CC=0.187，P=.049)、肿瘤大小(CC=−0.275，P=.003)和M状态(CC=0.190，P=.045)相关。在体外实验中，胰腺癌细胞的旁分泌作用导致成纤维细胞的形态激活和肿瘤细胞分化依赖的成纤维细胞生长增加。低分化PCCs的旁分泌作用导致NIH3T3成纤维细胞Vimentin表达上调。成纤维细胞的旁分泌作用促进了所有PCCs中癌细胞的运动。作为第二基质成分，成纤维细胞来源的ECM可显著抑制低分化PCCs的增殖，并上调ZEB1的表达。结论：在PDAC患者中，CAF分级阳性与阳性N状态、高LNR、阳性M状态、肿瘤较小相关。尽管PCCs和CAF的双边相互作用促进了肿瘤的进展，但ECM对PCC的生长造成了限制。综上所述，我们的研究揭示了基质成分的不同效应，并可能有助于解释先前研究的不同结果。
BACKGROUND AND AIM: Desmoplasia is a characteristic feature and a suspected mechanism of tumor progression in pancreatic ductal adenocarcinoma (PDAC). Main constituents of the stroma involve cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). The aim of this study was to dissect the interaction of CAFs, ECM, and PDAC cells in both an in vitro setting and a large-scale clinical cohort study. METHODS AND MATERIAL: Patients operated for PDAC were identified from our prospectively maintained clinical database. A standard pathology protocol was applied for pancreatoduodenectomy specimens also assessing CAF activation as either CAF grade 0 or CAF grade +. Interaction between a spectrum of pancreatic cancer cell lines (PCCs) and mouse embryonic fibroblasts (NIH 3T3) was assessed in a conditioned medium experimental setup. RESULTS: One hundred eleven patients operated for PDAC from 2001 to 2011 were identified. Univariate analysis disclosed CAF grade + (P = .030), positive M status (P < .001), and lymph node ratio (LNR) > 0.1 (P = .045) to impair overall survival. Independent prognostic factors were CAF grade (P = .050) and positive M status (P = .002). CAF grade correlated with N status (CC = 0.206, P = .030), LNR (CC = 0.187, P = .049), tumor size (CC = −0.275, P = .003), and M status (CC = 0.190, P = .045). In the in vitro setting, paracrine effects of pancreatic cancer cell resulted in morphological activation of fibroblasts and tumor cell differentiation–dependent increase of fibroblast growth. Paracrine effects of poorly differentiated PCCs led to an upregulation of Vimentin in NIH 3T3 fibroblasts. Paracrine effects of fibroblasts on their part promoted cancer cell motility in all PCCs. As the second stromal component, fibroblast-derived ECM resulted in significantly decreased proliferation depending on density and led to upregulation of ZEB1 in poorly differentiated PCCs. CONCLUSION: In PDAC patients, positive CAF grading was identified as a negative prognostic parameter correlating with positive N status, high LNR, positive M status, and smaller tumor size. Whereas bilateral interaction of PCCs and CAFs promotes tumor progression, ECM poses PCC growth restrictions. In summary, our study discloses differential effects of stromal components and may help to interpret heterogeneous results of former studies.