Expression of urocortin in pancreatic ductal adenocarcinoma and pancreatic intraepithelial neoplasia

Urocortin (UCN) is a 40‐aminoacid neuropeptide that regulates angiogenesis and inhibits cell proliferation. Our aim was to examine the relationship of UCN expression to the clinicopathological parameters of pancreatic ductal adenocarcinoma (PDAC) and histological grade of pancreatic intraepithelial neoplasia (PanIN). Tissue microarray was used to analyze UCN protein expression in 89 surgical specimens including 21 PanIN, 3 PDAC arising from PanIN, and 65 PDAC without PanIN. UCN immunoscores ranging from 0 to 12 were obtained by multiplying intensity (scored on a 3‐point scale) by the percentage of stained cells (scored on a 4‐point scale). Strong expression of UCN was detected in 5 specimens of non‐neoplastic pancreatic ductal epithelia. UCN immunoscore was significantly higher in PanIN‐1 than in PanIN‐2 and PanIN‐3 (p = 0.038) and significantly higher in well‐differentiated PDAC or early American Joint Committee on Cancer (AJCC) stage PDAC than in poorly differentiated or advanced stage PDAC (p = 0.025, p = 0.018). Higher expression of UCN correlates with PDAC tumor grade and AJCC pathologic stage as well as PanIN grade. Immunohistochemical assessment of UCN may help clinicians predict tumor recurrence rate and help pathologists make a proper diagnosis.     

The utility of Ki-67 expression in the differential diagnosis of prostatic intraepithelial neoplasia and ductal adenocarcinoma

Cribriform and/or papillary prostatic lesions observed on limited tissue, such as needle biopsy, can pose diagnostic dilemmas. One such area of difficulty is the distinction between papillary and/or cribriform prostatic high-grade prostatic intraepithelial neoplasia (HG-PIN) and ductal adenocarcinoma. Over 48 months, we identified 17 cases of ductal adenocarcinoma and 17 cases of HG-PIN from radical retropubic prostatectomy specimens. The HG-PIN lesions were in all cases associated with an acinar prostatic adenocarcinoma component. For each case, we evaluated the proliferative activity, assessed by Ki-67 immunohistochemistry. The majority (82%) of ductal adenocarcinomas were composed of mixed papillary and cribriform patterns, with the remaining demonstrating pure papillary or cribriform patterns. The HG-PIN lesions showed a papillary, cribriform, or mixed papillary/cribriform architecture. The proliferative activity, defined as Ki-67 labeling index, was statistically higher in ductal adenocarcinoma (mean 33%, range 21%-66%) as compared with HG-PIN (mean 6%, range 2%-15%), with no overlap in the Ki-67 indices (P = 0001). A combination of histological features and measurements of cellular proliferation may be helpful to distinguish HG-PIN from ductal adenocarcinoma in limited prostatic tissue samples.     

Molecular pathogenesis of pancreatic ductal adenocarcinoma

The statistics are alarming; pancreatic ductal adenocarcinoma (PDA) will be the second leading cause of death amongst all cancers by 2020. More worrisome is that incidence is on the rise, and without more effective cancer control of this disease, the trajectory of the virtually indistinguishable rates of incidence and mortality will remain the reality for years to come. Advances in genomics are beginning to clarify the key issues about the pathogenesis of this aggressive tumour type. New insights into classic pathogenic driver genes, such as KRAS, CDKN2A, TP53 and SMAD4, are portraying alternative roles for these genes beyond their function at the preneoplastic level including metastatic dissemination and chemoresistance. Clinically relevant molecular subtypes have recently emerged, which will aid oncologists in making more informed treatment decisions to improve outcomes in the future. A wealth of data surrounding these issues has been generated over the last 5 years. Below, we attempt to bring readers up to speed on recent research findings in PDA.     

Abnormal expression of Nek2 in pancreatic ductal adenocarcinoma: a novel marker for prognosis

Nek2 is a serine/threonine kinase that has a critical role in mitosis during the cell division process. Despite its importance in centrosome regulation and spindle formation, no direct binders are reported between human pancreatic cancer and Nek2 protein. Our aim in studying Nek2 expression and survival in PDA patients is to determine whether Nek2 is a valuable prognostic factor in PDA tumorigenesis. We found that Nek2 mRNA was elevated in PDA tissues. A high level of expression of Nek2 was significantly correlated with histological differentiation (P=0.042), lymph node metastasis (P=0.003) and tumor stage (P=0.001). Patients with a high Nek2 expression had a significantly worse overall survival (OS) than those patients with low Nek2 expression (P=0.002). Univariate and multivariate analysis revealed that high expression of Nek2 could serve as an independent predictor of poor prognosis. These results indicate that Nek2 could be a promising prognostic molecular marker and an attractive therapeutic target for PDA.     

PNMA1 promotes cell growth in human pancreatic ductal adenocarcinoma

Paraneoplastic Ma1 (PNMA1) is a member of an expanding family of ‘brain/testis’ proteins involved in an autoimmune disorder defined as paraneoplastic neurological syndrome (PNS). Although it is widely studied in PNS, little is known about the underlying clinical significance and biological function of PNMA1 in tumors. Here, we find that elevated PNMA1 expression is more commonly observed in pancreatic ductal adenocarcinoma (PDAC) cell lines, compared with normal pancreatic cell and tissues from pancreatic ductal adenocarcinoma patient. Besides, higher PNMA1 expression is closely correlated with large tumor size. Suppression of endogenous PNMA1 expression decreases cell viability and promotes cell apoptosis. Subsequent studies reveal that the PI3K/AKT, MAPK/ERK pathway and members of the anti-apoptotic Bcl-2 family may be involved in the pro-survival and anti-apoptotic effect of PNMA1 on PDAC. Taken together, this study provides evidence that PNMA1 is involved in tumor growth of pancreatic carcinoma and PNMA1-related pathways might represent a new treatment strategy.     

Concentrations of trace elements and KRAS mutations in pancreatic ductal adenocarcinoma

Trace elements are a possible risk factor for pancreatic ductal adenocarcinoma (PDAC). However, their role in the occurrence and persistence of KRAS mutations remains unstudied. There appear to be no studies analyzing biomarkers of trace elements and KRAS mutations in any human cancer. We aimed to determine whether patients with KRAS mutated and nonmutated tumors exhibit differences in concentrations of trace elements. Incident cases of PDAC were prospectively identified in five hospitals in Spain. KRAS mutational status was determined through polymerase chain reaction from tumor tissue. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Concentrations of trace elements were compared in 78 PDAC cases and 416 hospital-based controls (case–control analyses), and between 17 KRAS wild-type tumors and 61 KRAS mutated tumors (case–case analyses). Higher levels of iron, arsenic, and vanadium were associated with a statistically nonsignificant increased risk of a KRAS wild-type PDAC (OR for higher tertile of arsenic = 3.37, 95% CI 0.98–11.57). Lower levels of nickel and manganese were associated with a statistically significant higher risk of a KRAS mutated PDAC (OR for manganese = 0.34, 95% CI 0.14–0.80). Higher levels of selenium appeared protective for both mutated and KRAS wild-type PDAC. Higher levels of cadmium and lead were clear risk factors for both KRAS mutated and wild-type cases. This is the first study analyzing biomarkers of trace elements and KRAS mutations in any human cancer. Concentrations of trace elements differed markedly between PDAC cases with and without mutations in codon 12 of the KRAS oncogene, thus suggesting a role for trace elements in pancreatic and perhaps other cancers with such mutations. Environ. Mol. Mutagen., 60:693–703, 2019. © 2019 Wiley Periodicals, Inc.     

胰腺癌中主要的基因改变

胰腺导管腺癌是胰腺癌中最常见的组织学类型,其发病隐匿,预后差,死亡率高,治疗手段有限。目前对其致病机制的研究很多,遗传因素和环境因素所造成的分子遗传学改变在其中凸显重要,越来越多的发现都深入到了基因分子水平。对于这些已发现的基因改变,有些已通过体内体外实验予以验证,有些仍未明确,现对其中4个主要通路的特征性分子改变以及相关途径的认识做一简要概括,进一步明确这些基因改变在胰腺癌发病过程中的作用及其研究的现状。     

长链非编码RNA CCHE1在胰腺导管腺癌中的表达及临床意义

目的 检测长链非编码RNA(lncRNA)CCHE1在胰腺导管腺癌(PDAC)细胞和组织中的表达,探讨lncRNA CCHE1与PDAC临床病理特征及预后间的关系.方法 RT-PCR检测PDAC组织及配对癌旁组织以及PDAC细胞和胰腺导管上皮细胞中lncRNA CCHE1的表达;利用单因素方差分析探讨lncRNA CC...     

Association of chloride intracellular channel 4 and Indian hedgehog proteins with survival of patients with pancreatic ductal adenocarcinoma

Pancreatic cancer is the fourth most common cause of cancer‐related mortality. Novel molecular biomarkers need to be identified for personalized medicine and to improve survival. The aim of this study was to examine chloride intracellular channel 4 (CLIC4) and Indian Hedgehog (Ihh) expression in benign and malignant lesions of the pancreas and to examine the eventual association between CLIC4 and Ihh expression, with clinicopathological features and prognosis of pancreatic cancer. A retrospective study of specimens collected from January 2000 to December 2011 at the Department of Pathology of the Second and Third Xiangya Hospitals, Central South University was undertaken to explore this question. Immunohistochemistry of CLIC4 and Ihh was performed with EnVision^? in 106 pancreatic ductal adenocarcinoma specimens, 35 paracancer samples (2 cm away from the tumour, when possible or available), 55 benign lesions and 13 normal tissue samples. CLIC4 and Ihh expression in pancreatic ductal adenocarcinoma were significantly higher than in paracancer tissue and benign lesions (CLIC4: P = 0.009 and Ihh: P < 0.0001; CLIC4: P = 0.0004 and Ihh: P = 0.0001 respectively). CLIC4 and Ihh expression was negative in normal pancreatic tissues. The expression of CLIC4 and Ihh was associated significantly with tumour grade, lymph node metastasis, tumour invasion and poor overall survival. Thus CLIC4 and Ihh could serve as biological markers for the progression, metastasis and/or invasiveness of pancreatic ductal adenocarcinoma.     

前列腺上皮内肿瘤与前列腺癌的病理形态学研究

目的：探讨前列腺上皮内肿瘤（ＰＩＮ）恙前列腺癌的关系。方法：用常规ＨＥ染色、免疫组化、电镜方法，对１１３例前列腺标本进行形态学研究。结果：（１）ＰＩＮ由分泌细胞异型增生所致，其１、２级基底细胞及些在膜完整，３级则为局限性缺失和断裂。（２）ＰＩＮ检出率剪列腺癌例中明显高于非癌例中，癌旁高于远癌区，提示与癌关系密切。３）免疫组化对ＰＩＮ的的级、ＰＩＮ与癌的鉴别有意义。（４）利用电镜观察癌细胞微足状浸润     

High expression of GRK3 is associated with favorable prognosis in pancreatic ductal adenocarcinoma

Background

It was found that G-protein-coupled receptor kinase 3 (GRK3) played key biological roles in some cancers. However, its associations with clinicopathologic features and prognosis in pancreatic ductal adenocarcinoma (PDAC) remain unknown.

胰腺癌上皮与间质:环境选择与肿瘤演化

胰腺癌(胰腺导管腺癌,pancreatic ductal adenocarcinoma,PDAC)的一个显著的特征是其丰富的间质反应.胰腺星状细胞(pancreatic stellate cells,PSCs)在胰腺癌的间质反应中是重要的细胞成分,大量的体内外实验表明间质反应在胰腺癌的发展、浸润、转移、耐药性等方面均有重要作用.而针对间质及在间质反应中发挥关键作用的旁分泌Hedgehog通路的临床试验却没有取得预期的效果.更有甚,去除胰腺星状细胞后加速了胰腺癌的发生发展.胰腺癌基质在肿瘤发生发展中的不同阶段表现出相悖的作用.因此必须进一步探究胰腺癌与间质关系,寻找可能的靶点,在降低胰腺癌对放化疗耐药性、延长胰腺癌中位生存期等方面提供有效指导.