胰腺导管腺癌肿瘤间质特征与肿瘤细胞PIN1表达的相关性
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摘要
目的探讨胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDAC)肿瘤间质特征与临床病理特征,及与肿瘤细胞脯氨酸顺反异构酶PIN1表达的关系。方法收集2010～2016年PDAC临床样本120例,评价组织切片肿瘤间质特征,构建组织芯片,行肿瘤细胞PIN1免疫组化染色,并分析PDAC的临床病理特征。结果 120例PDAC患者中,肿瘤间质成熟型33例,不成熟型53例,中间型34例;低肿瘤间质容量85例,高肿瘤间质容量35例;肿瘤细胞PIN1低表达48例,高表达72例。肿瘤间质成熟度与PDAC组织学分级(P=0. 029)、淋巴结转移(P=0. 027)有相关性,肿瘤间质容量与PDAC组织学分级显著相关(P<0. 000 1)。肿瘤间质成熟度与肿瘤间质容量(P <0. 000 1)和肿瘤细胞PIN1表达有相关性。Kaplan-Meier生存分析显示PDAC中具有肿瘤间质成熟型(Log-rank=6. 03,HR=1. 83,95%CI=1. 13～2. 98,P=0. 014)和高肿瘤间质容量(Log-rank=15. 23,HR=2. 72,95%CI=1. 74～4. 27,P <0. 000 1)的患者预后较好。Cox多因素分析显示肿瘤间质容量是患者独立的预后指标。结论 PDAC肿瘤间质特征与PDAC预后差的临床病理特征及肿瘤细胞PIN1表达有关。PIN1可能参与PDAC肿瘤间质微环境的重塑,有望成为其靶向治疗的潜在分子。
Purpose To study the relationships between the features of tumor stroma and the clinico-pathological parameters and PIN1 expression of tumor cells in pancreatic ductual adenocarcinoma( PDAC). Methods A total of 120 cases of PDAC samples from 2010 to 2016 were collected to evaluate the characteristics of tumor stroma. Tissue microarray was constructed and PIN1 protein was stained by immunohistochemistry and multiple clinico-pathological parameters were recorded and analyzed. Results Of 120 cases of PDAC,there were 33 cases of mature type,53 cases of immature type,and 34 cases of intermediate type respectively. 85 cases were low stromal volume,and 35 cases were high stromal volume. For PIN1 expression in tumor cells,48 were low expression and 72 high expression. The degree of tumor stromal maturity was significantly correlated with histological grade( P = 0. 029) and p N( P = 0. 027). The tumor stromal volume was significantly correlated with histologi-cal degree( P < 0. 000 1). Degree of stromal maturity was closely related to the stromal volume( P < 0. 000 1) and the PIN1 expression in tumor cells( P = 0. 026). Kaplan-Meier survival analysis showed patients of PDAC with stromal maturity( Log-rank = 6. 03,HR = 1. 83,95% CI = 1. 13-2. 98,P =0. 014) and high stromal volume( Log-rank = 15. 23,HR =2. 72,95% CI = 1. 74-4. 27,P < 0. 000 1) had better outcomes. Cox multivariate regression analysis showed tumor stromal volume was an independent prognostic factors for patients.Conclusion Tumor stroma is associated with poor clinico-pathological features and PIN1 expression of tumor cells in PDAC.PIN1 may be a conditioner in remolding stromal microenvironment and be a potential new targets for the treatment of PDAC.
Purpose To study the relationships between the features of tumor stroma and the clinico-pathological parameters and PIN1 expression of tumor cells in pancreatic ductual adenocarcinoma( PDAC). Methods A total of 120 cases of PDAC samples from 2010 to 2016 were collected to evaluate the characteristics of tumor stroma. Tissue microarray was constructed and PIN1 protein was stained by immunohistochemistry and multiple clinico-pathological parameters were recorded and analyzed. Results Of 120 cases of PDAC,there were 33 cases of mature type,53 cases of immature type,and 34 cases of intermediate type respectively. 85 cases were low stromal volume,and 35 cases were high stromal volume. For PIN1 expression in tumor cells,48 were low expression and 72 high expression. The degree of tumor stromal maturity was significantly correlated with histological grade( P = 0. 029) and p N( P = 0. 027). The tumor stromal volume was significantly correlated with histologi-cal degree( P < 0. 000 1). Degree of stromal maturity was closely related to the stromal volume( P < 0. 000 1) and the PIN1 expression in tumor cells( P = 0. 026). Kaplan-Meier survival analysis showed patients of PDAC with stromal maturity( Log-rank = 6. 03,HR = 1. 83,95% CI = 1. 13-2. 98,P =0. 014) and high stromal volume( Log-rank = 15. 23,HR =2. 72,95% CI = 1. 74-4. 27,P < 0. 000 1) had better outcomes. Cox multivariate regression analysis showed tumor stromal volume was an independent prognostic factors for patients.Conclusion Tumor stroma is associated with poor clinico-pathological features and PIN1 expression of tumor cells in PDAC.PIN1 may be a conditioner in remolding stromal microenvironment and be a potential new targets for the treatment of PDAC.
引文
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[15] Von A D,Bhagat T D,Nagrath D,et al. The role of stromal cancer-associated fibroblasts in pancreatic cancer[J]. J Hematol Oncol,2017,10(1):76-83.
[2] Bolm L,Cigolla S,Wittel U A,et al. The role of fibroblasts in pancreatic cancer:extracellular matrix versus paracrine factors[J]. Transl Oncol,2017,10(4):578-588.
[3] Knudsen E S,Vail P,Balaji U,et al. Stratification of pancreatic ductal adenocarcinoma:combinatorial genetic,stromal,and immunologic markers[J]. Clin Cancer Res,2017,23(15):4429-4440.
[4] Carapuca E F,Gemenetzidis E,Feig C,et al. Anti-stromaltreatment together with chemotherapy targets multiple signallingpathways in pancreatic adenocarcinoma[J]. J Pathol,2016,239(3):286-296.
[5] Wei S,Kozono S,Kats L,et al. Active Pin1 is a key target of alltrans retinoic acid in acute promyelocytic leukemia and breast cancer[J]. Nat Med,2015,21(5):457-466.
[6] Lu K P,Hanes S D,Hunter T. A human peptidyl-prolyl isomerase essential for regulation of mitosis[J]. Nature,1996,380(6574):544-547.
[7] Wei S,Yoshida N,Finn G,et al. Pin1-targeted therapy for systemic lupus erythematosus[J]. Arthritis Rheumatol,2016,68(10):2503-2513.
[8] Bosman F T,Carneiro F,Hruban R H,et al. WHO classification of tumours of the digestive system[M]. 4th ed. Lyon:IARC Press,2010:279-291.
[9] Chen L Y,Tsang J Y,Ni Y B,et al. Bcl2 and Ki67 refine prognostication in luminal breast cancers[J]. Breast Cancer Res Treat,2015,149(3):631-643.
[10]王甜甜,陆建波,普苹,等.癌相关成纤维细胞对结肠癌细胞增殖侵袭能力的影响[J].临床与实验病理学杂志,2013,29(5):511-515.
[11] Zdemir B C,Pentcheva-Hoang T,Carstens J L,et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival[J]. Cancer Cell,2014,16,25(6):719-734.
[12] Rhim A D,Oberstein P E,Thomas D H,et al. Stromal elements act to restrain,rather than support,pancreatic ductal adenocarcinoma[J]. Cancer Cell,2014,25(6):735-747.
[13] Attieh Y,Clark A G,Grass C,et al. Cancer-associated fibroblasts lead tumor invasion through integrin-b3-dependent fibronectin assembly[J]. J Cell Biol,2017,216(11):3509-3520.
[14] Zhou X Z,Lu K P. The isomerase PIN1 controls numerous cancerdriving pathways and is a unique drug target[J]. Nat Rev Cancer,2016,16(7):463-478.
[15] Von A D,Bhagat T D,Nagrath D,et al. The role of stromal cancer-associated fibroblasts in pancreatic cancer[J]. J Hematol Oncol,2017,10(1):76-83.