Dall'Ora Massimiliano, Rovesti Giulia, Reggiani Bonetti Luca, Casari Giulia, Banchelli Federico, Fabbiani Luca, Veronesi Elena, Petrachi Tiziana, Magistri Paolo, Di Benedetto Fabrizio, Spallanzani Andrea, Chiavelli Chiara, Spano Maria Carlotta, Maiorana Antonino, Dominici Massimo, Grisendi Giulia
Rigenerand S.r.l. Medolla 41036, Italy.
Division of Oncology, Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences of Children & Adults, University of Modena and Reggio Emilia Modena 41124, Italy.
Am J Cancer Res. 2021 Sep 15;11(9):4500-4514. eCollection 2021.
This study assesses the expression of all TNF-related apoptosis-inducing ligand (TRAIL) receptors in pancreatic ductal adenocarcinoma (PDAC) tumor tissue. We aimed to include TRAIL receptor expression as an inclusion parameter in a future clinical study using a TRAIL-based therapy approach for PDAC patients. Considering the emerging influence of PDAC desmoplastic stroma on the efficacy of anti-PDAC therapies, this analysis was extended to tumor stromal cells. Additionally, we performed PDAC stroma characterization. Our retrospective cohort study (N=50) included patients with histologically confirmed PDAC who underwent surgery. The expression of TRAIL receptors (DR4, DR5, DcR1, DcR2, and OPG) in tumor and stromal cells was evaluated by immunohistochemistry (IHC). The amount of tumor stroma was assessed by anti-vimentin IHC and Mallory's trichrome staining. The prognostic impact was determined by the univariate Cox proportional hazards regression model. An extensive expression of functional receptors DR4 and DR5 and a variable expression of decoy receptors were detected in PDAC tumor and stromal cells. Functional receptors were detected also in metastatic tumor and stromal cells. A poor prognosis was associated with low or absent expression of decoy receptors in tumor cells of primary PDAC. After assessing that almost 80% of tumor mass was composed of stroma, we correlated a cellular-dense stroma in primary PDAC with reduced relapse-free survival. We demonstrated that TRAIL functional receptors are widely expressed in PDAC, representing a promising target for TRAIL-based therapies. Further, we demonstrated that a low expression of DcR1 and the absence of OPG in tumor cells, as well as a cellular-dense tumor stroma, could negatively impact the prognosis of PDAC patients.
本研究评估了胰腺导管腺癌(PDAC)肿瘤组织中所有肿瘤坏死因子相关凋亡诱导配体(TRAIL)受体的表达情况。我们旨在将TRAIL受体表达作为一个纳入参数,用于未来一项针对PDAC患者采用基于TRAIL治疗方法的临床研究。考虑到PDAC促纤维增生性基质对PDAC治疗疗效的影响日益显现,本分析扩展至肿瘤基质细胞。此外,我们还对PDAC基质进行了特征描述。我们的回顾性队列研究(N = 50)纳入了经组织学确诊且接受手术的PDAC患者。通过免疫组织化学(IHC)评估肿瘤和基质细胞中TRAIL受体(DR4、DR5、DcR1、DcR2和骨保护素(OPG))的表达。通过抗波形蛋白IHC和马洛里三色染色评估肿瘤基质的数量。通过单变量Cox比例风险回归模型确定预后影响。在PDAC肿瘤和基质细胞中检测到功能性受体DR4和DR5的广泛表达以及诱饵受体的可变表达。在转移性肿瘤和基质细胞中也检测到了功能性受体。原发性PDAC肿瘤细胞中诱饵受体低表达或无表达与预后不良相关。在评估几乎80%的肿瘤块由基质组成后,我们发现原发性PDAC中细胞密集的基质与无复发生存期缩短相关。我们证明TRAIL功能性受体在PDAC中广泛表达,是基于TRAIL治疗的一个有前景的靶点。此外,我们证明肿瘤细胞中DcR1低表达和OPG缺失以及细胞密集的肿瘤基质可能对PDAC患者的预后产生负面影响。