Bolm Louisa, Cigolla Simon, Wittel Uwe A, Hopt Ulrich T, Keck Tobias, Rades Dirk, Bronsert Peter, Wellner Ulrich Friedrich
Department of Surgery, University of Luebeck, Luebeck, Germany.
Department of Surgery, University of Luebeck, Luebeck, Germany.
Transl Oncol. 2017 Aug;10(4):578-588. doi: 10.1016/j.tranon.2017.04.009. Epub 2017 Jun 26.
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.
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.
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.
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.
促纤维组织增生是胰腺导管腺癌（PDAC）的一个特征性表现及肿瘤进展的一种推测机制。基质的主要成分包括癌症相关成纤维细胞（CAFs）和细胞外基质（ECM）。本研究的目的是在体外环境和大规模临床队列研究中剖析CAFs、ECM与PDAC细胞之间的相互作用。
从我们前瞻性维护的临床数据库中识别出接受PDAC手术的患者。对胰十二指肠切除术标本应用标准病理方案，同时评估CAF激活情况，分为CAF 0级或CAF +级。在条件培养基实验设置中评估一系列胰腺癌细胞系（PCCs）与小鼠胚胎成纤维细胞（NIH 3T3）之间的相互作用。
确定了2001年至2011年期间接受PDAC手术的111例患者。单因素分析显示CAF +级（P = 0.030）、M状态阳性（P < 0.001）和淋巴结比率（LNR）> 0.1（P = 0.045）会损害总生存期。独立预后因素为CAF分级（P = 0.050）和M状态阳性（P = 0.002）。CAF分级与N状态（CC = 0.206，P = 0.030）、LNR（CC = 0.187，P = 0.049）、肿瘤大小（CC = -0.275，P = 0.003）和M状态（CC = 0.190，P = 0.045）相关。在体外环境中，胰腺癌细胞的旁分泌作用导致成纤维细胞形态激活和成纤维细胞生长的肿瘤细胞分化依赖性增加。低分化PCCs的旁分泌作用导致NIH 3T3成纤维细胞中波形蛋白上调。成纤维细胞的旁分泌作用反过来促进所有PCCs中的癌细胞运动。作为第二种基质成分，成纤维细胞衍生的ECM根据密度导致增殖显著降低，并导致低分化PCCs中ZEB1上调。
在PDAC患者中，CAF分级阳性被确定为与N状态阳性、高LNR、M状态阳性和较小肿瘤大小相关的负面预后参数。虽然PCCs与CAFs的双向相互作用促进肿瘤进展，但ECM对PCCs生长构成限制。总之，我们的研究揭示了基质成分的不同作用，并可能有助于解释先前研究的异质性结果。
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