Roles of Carbonic Anhydrase IX in Development of Pancreatic Cancer

The aim of this study was to study the effects of carbonic anhydrase IX (CA IX) towards the invasion and metastasis of pancreatic cancer. The expressions of CA IX in 58 cases of pancreatic cancer and paired paracancerous normal tissues, obtained from 2005 to 2012 in the first Affiliated Hospital of China Medical University, were detected, as well as its expressions in different pancreatic cancer cell lines, aiming to detect the impacts of CA IX silencing towards the invasion and metastasis of pancreatic cancer cells. The CA IX expressions in 58 pancreatic cancer cases were higher than those in the paired paracancerous normal tissues (P?<?0.01), and positively correlated with the tumor size and the UICC staging UICC (P?<?0.05), the multivariate analysis showed that the high expression of CA IX was the independent risk factor towards the prognosis of pancreatic cancer (P?<?0.05). The CA IX was highly expressed in AxPC–1 and Miapaca–2, and the interference effects were significant. CA IX silencing could significantly inhibit the invasion and metastasis of AxPC-1 and Miapaca. We support a pro-tumor role of CA IX in the development and progression of pancreatic cancer.     

血清碳酸酐酶IX检测对肺癌的诊断意义

背景与目的碳酸酐酶IX(carbonic anhydrase IX,CAIX)是一种跨膜蛋白,参与肿瘤细胞的代谢过程。其在少数正常组织中低表达,但在多种恶性肿瘤组织中广泛表达。检测CAIX在肺癌患者血清中的含量,探讨其对肺癌的诊断价值,分析不同病理类型及TNM分期肺癌患者血清CAIX含量是否存在差异。方法选取47例肺癌患者和31例健康体检者为研究对象,用酶联免疫吸附测定(enzyme linked immunosorbent assay,ELISA)法检测其血清CAIX含量,根据病理类型及TNM分期分组,比较各组血清CAIX差异;绘制血清CAIX诊断肺癌的受试者工作特征曲线(receiver operating characteristic curve,ROC)。结果肺癌组较健康对照组血清CAIX含量明显增高(P<0.001);鳞癌和小细胞癌患者血清CAIX含量明显高于腺癌患者。I期+II期与III期+IV期的肺癌患者血清CAIX含量比较,未发现两者间的差异有统计学意义;血清CAIX诊断肺癌的ROC曲线下面积为0.961,当血清中CAIX阈值为115.115 pg/m L时,敏感度和特异度分别为95.7%和90.3%。结论用ELISA法检测患者血清CAIX有助于肺癌诊断,且具有较高的敏感性和特异性。     

Characterization of a New Primary Human Pancreatic Tumor Line

A primary human pancreatic tumor line (BxPC-3) has been established from a biopsy specimen of a histologically confirmed adenocarcinoma of the body of the pancreas. Tumorigenicity was proven by xenograft in athymic nude mice. Upon re-establishment of tumor xenografts in tissue culture, the epithelial tumor cells retained their original morphology. Histopathologically, the tumors grown in nude mice exhibited the original characteristics of the primary adenocarcinoma in the patient, producing traceable mucin and displaying moderately well to poorly differentiated adenocarcinomas with occasional lymphocytic infiltrations at the tumor peripheries. Furthermore, the tumor xenografts differentially expressed carcinoembryonic antigen, human pancreas cancer-associated antigen, and human pancreas-specific antigen. Karyotyping and glucose-6-phosphate dehydrogenase isoenzyme characterization revealed that this tumor line was of human origin and devoid of HeLa cell contamination. The BxPC-3 tumor line has been maintained for more than four years in our laboratory and represents a valuable model for primary human pancreatic cancer.     

Carbonic anhydrase IX as a marker for poor prognosis in soft tissue sarcoma.

PURPOSE: Hypoxia is associated with malignant progression and poor outcome in several human tumors, including soft tissue sarcoma. Recent studies have suggested that carbonic anhydrase (CA) IX is an intrinsic marker of hypoxia, and that CA IX correlates with poor prognosis in several types of carcinoma. The aim of this study was to quantify the extent of CA IX expression and to investigate whether CA IX is a marker for poor prognosis in soft tissue sarcoma patients at high risk of developing metastasis. EXPERIMENTAL DESIGN: Archival paraffin-embedded blocks were retrieved from 47 patients with deep, large, high-grade soft tissue sarcoma. Sections from two separate and representative tumor areas were immunostained for CA IX, and the CA IX-positive area fraction was quantified by image analysis, excluding areas of normal stroma and necrosis that were identified from serial H&E-stained sections. Patients were then subject to survival analysis. RESULTS: CA IX-positive area fractions of viable tumor tissue varied significantly between tumors (range, 0-0.23; median, 0.004), with positive membranous CA IX staining in 66% (31 of 47) of the tumors. Patients with CA IX-positive tumors had a significantly lower disease-specific and overall survival than patients with CA IX-negative tumors (P = 0.033 and P = 0.044, respectively). CONCLUSIONS: These data suggest that CA IX, a potential intrinsic marker of hypoxia, predicts for poor prognosis in patients with deep, large, high-grade soft tissue sarcoma. Larger studies are required to determine whether CA IX has independent prognostic value in this group of tumors.     

The Presence of a Fibrotic Focus in Invasive Breast Carcinoma Correlates with the Expression of Carbonic Anhydrase IX and is a Marker of Hypoxia and Poor Prognosis

The value of the fibrotic focus (FF) as a marker of intra-tumoral hypoxia in invasive breast carcinoma was assessed by studying its relationship with the expression of the hypoxia-induced carbonic anhydrase IX (CA IX), angiogenesis indices and prognosis.CA IX expression was immunohistochemically detected in 2 independent study groups, totaling 184 patients, and correlated with tumor characteristics, angiogenesis related parameters and patient outcome by univariate analysis.CA IX immunostaining scores in carcinoma cells and in tumoral fibroblasts were significantly higher in expansively growing tumors (p = 0.0001 and p < 10^–4, respectively), containing an FF (p = 0.0004 and p < 10^–4) and showing high histological grade (p = 0.016 and p = 0.0006).Microvessel density, quantified by Chalkley counting, was correlated with CA IX expression both in the carcinoma cells and in the fibroblasts (p = 0.0076 and p = 0.0025) and with the presence and relative size of an FF (p = 0.006). The fraction of proliferating endothelial cells was positively correlated with CA IX scores in the fibroblasts (r = 0.4, p = 0.02) and with the presence of an FF (p = 0.02). CA IX scores in the fibroblasts – and to a lesser extent in the carcinoma cells – were associated with a higher relapse rate (p = 0.006) and a worse overall survival (p = 0.003). The highest CA IX immunostaining scores were found in the fibroblasts of large FF occupying more than one-third of the tumor. A large FF was associated with worse overall survival in a consecutive patient group (p = 0.01) and with shorter disease-free (p = 0.02) and overall survival (p = 0.0005) in T_1-2N₀ breast cancer patients.The strong association of CA IX expression with the presence of an FF shows that the latter is a marker of intra-tumoral hypoxia. FF is useful as a surrogate marker of hypoxia-driven ongoing angiogenesis and is associated with a higher relapse rate and a worse overall survival.     

GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth

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外泌体miRNA作为肿瘤标志物在消化系肿瘤的研究进展

外泌体是由活细胞分泌,普遍存在于唾液、血浆和乳汁等体液中的纳米级囊泡。外泌体中含有诸多功能性的DNA、蛋白质以及非编码RNA等活性物质,外泌体可以在细胞间穿梭广泛参与细胞间信息传递和物质交换。研究发现肿瘤外泌体中一些特定miRNA具有生物学特性和靶向特异性,可以调节机体在代谢紊乱中的生物活动,从多方面参与肿瘤发生发展,具有成为肿瘤治疗和预后标志物的潜力。因此,探寻外泌体中特定miRNA在消化系统肿瘤中的作用及其作为生物标志物的可能性,从而为消化系统肿瘤的预防和诊疗提供新思路具有重要意义。全文针对外泌体miRNA在消化系统肿瘤的研究进展作一综述。     

环状RNA作为脑肿瘤潜在生物学标志物的研究进展

环状RNA(circular RNA,circRNA)是一类无游离5′端和3′端的共价闭合的非编码RNA,具有丰富性、稳定性、保守性和组织特异性等结构特点,circRNA与细胞增殖、凋亡、血管生成和转移等方面都有着密不可分的联系。脑肿瘤因为其独特的微环境造成了其发生发展机制的特殊性。研究circRNA与脑肿瘤发生发展的机制,必将促进对脑肿瘤诊断、治疗预后等多方面的发展。全文综述circRNA在常见脑肿瘤（胶质瘤、垂体瘤和髓母细胞瘤）中的表达情况及其靶向miRNA和后续信号通路,并概述其作用结果,总结circRNA作为多种脑肿瘤的潜在生物学标志物。     

Initiating Activity of Diethylnitrosamine in a Rapid Production Model for Pancreatic Carcinomas in Syrian Hamsters

The potential initiating activity of diethylnitrosamine (DEN) was studied in a rapid production model for pancreatic carcinogenesis in hamsters developed in our laboratory incorporating the principle of selection based on resistance to cytotoxicity, originally demonstrated for liver carcinogenesis in rats. Female Syrian golden hamsters were given DEN at a dose of 100 mg/kg body weight or N-nitrosobis-(2-oxopropyI)amine (BOP) at a dose of 70 mg/kg body weight as initiators followed by 3 cycles of augmentation pressure (choline-deficient diet combined with DL-ethionine, L-methionine upon return to basal diet and then administration of 20 mg/kg body weight BOP), and killed 10 weeks after the beginning of the experiment. DEN followed by the augmentation pressure induced a 65% incidence of total pancreatic lesions including 15% carcinomas, while BOP followed by the augmentation pressure induced 100% incidence of total pancreatic lesions and 84.2% for carcinomas. These yields were significantly greater than those observed for augmentation pressure alone. The results thus indicate that DEN possesses weak initiating activity for pancreatic carcinogenesis under the present experimental conditions.     

Neuroendocrine Pancreatic Tumors Clinical Findings in a prospective study of 84 patients

Endocrine pancreatic tumors are slowly growing neuroendocrine neoplasms with a malignant potential which may cause symptoms such as hypoglycemia, multiple ulcers, diarrhea, flush, hyperglycemia and skin rash. A prospective study was performed on 84 patients with endocrine pancreatic tumors. In 59 patients (70%) the tumors were malignant. Of the 84 patients, 23 had insulinomas, 25 gastrinomas, 20 nonfunctioning tumors, 14 the WDHA syndrome, I somatostatinoma and 1 glucagonoma. The median age at diagnosis was 53 years and the median delay from first symptom to diagnosis was 2 years. The most common site of the pancreatic primary tumor was the tail (41 %), and metastases were most frequently located in the liver (60%) and lymph nodes (44%). Plasma chromogranin A + B was elevated in 94%, serum pancreatic polypeptide (PP) in 74%, plasma neurotensin in 67% and serum gastrin in 62%. Serum HCG-aL and -bT subunits were elevated in 41 and 30% respectively, all except 3 having a verified malignant tumor. The median survival from first symptom and diagnosis was 14.2 and 8.7 years respectively. Patients with MEN-1 had a significantly better survival from diagnosis than sporadic cases (median 15.1 versus 5.8 years). Patients who received interferon after failing chemotherapy had a significantly better survival than those given chemotherapy alone (5-year survival 65 and 50% respectively).     

Extensive Intra-tumor Heterogeneity in Primary Human Glial Tumors as a Result of Locus Non-specific Genomic Alterations

Genomic changes are a hallmark of the neoplastic process. These range from alterations at specific loci and defined karyotypic changes which influence tumor behavior to generalized alterations exemplified by microsatellite instability. Generalized genomic changes within a tumor would be evidence in favor of the mutator hypothesis which postulates a role for such extensive changes during tumorigenesis. In this report, we have used the DNA fingerprinting technique of randomly amplified polymorphic DNA (RAPD) analysis to study genomic alterations within primary human astrocytic tumors (gliomas) in a locus non-specific manner. The RAPD fingerprinting profile of consecutive segments of tumors 2mm across was studied; 17 astrocytic (high- and low-grade) tumors were sectioned end to end. Tissue from 50 consecutive sections, 40µm thick (total 2mm across), was pooled and taken to be a tumor compartment. DNA was subjected to RAPD amplification by 15 random 10-mer primers.A tumor segment was taken to have a DNA fingerprinting pattern different from others in the same specimen when its RAPD profile differed from others by at least one band of one RAPD reaction. All but one of the tumors showed compartments with a unique genetic profile, indicating genomic instability leading to widespread intra-tumor genetic heterogeneity. Eight tumors were also studied for loss of heterozygosity (LOH) of the p53 and D17S379 loci in the different segments as examples of alteration of specific tumor influencing loci. Three showed LOH of p53, which was limited to only one compartment of each tumor.The extensive intra-tumor genetic instability detected in this study is suggestive of the overall high rate of change in the genomes of tumors including those of a lower grade. It is hypothesized that some of these altered clones, which manifest as zones of heterogeneity in a solid tumor, may accumulate changes at loci known to influence tumor behavior, and thus clinical outcome.     

Quantitative Evaluation of Proliferative Potential Using Flow Cytometry Reveals Intratumoral Heterogeneity and Its Relevance to Tumor Characteristics in Vestibular Schwannomas

This study sought to explore the existence and clinical significance of intratumoral heterogeneity of proliferative potential in vestibular schwannoma (VS). Rapid intraoperative flow cytometry was utilized with raw samples to measure the proliferative ability of VS. The proliferation index (PI) was defined as the ratio of the number of cells with greater than normal DNA content to the total number of cells. A total of 66 specimens (26 from the intrameatal portion and 40 from the cisternal portion) were obtained from 34 patients with VS. There was a moderate correlation between the PI and MIB-1 labelling index values (R = 0.57, p < 0.0001). In contrast, the patterns of heterogeneity, represented by the proportion of intrameatal PI to cisternal PI, were associated with tumor size (p = 0.03). In addition, preoperative hearing tended to be poor in cases where the intrameatal PI was higher than the cisternal PI (p = 0.06). Our data demonstrated the presence of intratumoral heterogeneity of proliferative potential in VS and its relationship with tumor characteristics. The results of this study may advocate the resection of the intrameatal portion of large VSs treated with planned subtotal resection, especially in cases of poor preoperative hearing function.     

Importance of Volumetric Measurement Processes in Oncology Imaging Trials for Screening and Evaluation of Tumors as Per Response Evaluation Criteria in Solid Tumors

Cancer, like any disease, is a pathologic biological process. Drugs are designed to interfere with the pathologicprocess and should therefore also be validated using a functional screening method directed at these processes.Screening for cancers at an appropriate time and also evaluating results is also very important. Volumetricmeasurement helps in better screening and evaluation of tumors. Volumetry is a process of quantification of thetumors by identification (pre-cancerous or target lesion) and measurement. Volumetric image analysis allowsan accurate, precise, sensitive, and medically valuable assessment of tumor response. It also helps in identifyingpossible outcomes such disease progression (PD) or complete response as per Response Evaluation Criteria inSolid Tumors (RECIST).     

Prognostic Role of Circulating Tumor Cells in Patients with Pancreatic Cancer: a Meta-analysis

Background: Isolation and characterization of circulating tumor cells (CTCs) in patients suffering from a variety of different cancers have become hot biomarker topics. In this study, we evaluated the prognostic value of CTCs in pancreatic cancer. Materials and Methods: Initial literature was identified using Medlineand EMBASE. The primary data were hazard ratios (HRs) with 95% confidence intervals (CIs) of survival outcomes, including overall survival (OS) and progression free survival/recurrence free survival (PFS/RFS). Results: A total of 9 eligible studies were included in this meta-analysis, published between 2002 and 2013. The estimated pooled HR and 95%CI for OS for all studies was 1.64 (95%CI 1.39-1.94, p<0.00001) and the pooled HR and 95%CI for RFS/DFS was 2.36 (95%CI 1.41-3.96, p<0.00001). The HRs and 95%CIs for OS and RFS/DFS in patients before treatment were 1.93 (95%CI 1.26-2.96, p=0.003) and 1.82 (95%CI 1.22-2.72, p=0.003), respectively. In patients receiving treatment, the HRs and 95%CI for OS and RFS/DFS were 1.37 (95%CI 1.00-1.86, p=0.05) and 1.89 (95%CI 1.01-3.51, p=0.05), respectively. Moreover, the pooled HR and 95%CI for OS in the post-treatment group was 2.20 (95%CI 0.80-6.02, p=0.13) and the pooled HR for RFS/DFS was 8.36 (95%CI 3.22-21.67, p<0.0001). Conclusions: The meta-analysis provided strong evidence supporting the proposition that CTCs detected in peripheral blood have a fine predictive role in pancreatic patients especially on the time point of post-treatment.     

Anti-tumor Initiating Potential of Andrographolide in 7,12-dimethylbenz[a]anthracene Induced Hamster Buccal Pouch Carcinogenesis

The aim of the study was to investigate the chemopreventive potential of andrographolide in 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Oral tumors developed in the buccal pouch ofgolden Syrian hamsters at a 100% incidence on painting with 0.5% DMBA in liquid paraffin three times a weekfor 14 weeks. Marked abnormalities in the status of detoxification enzymes, lipid perxodiation and antioxidantswere noticed in hamsters treated with DMBA alone. Oral administration of andrographolide at a dose of 50 mg/kg bw to hamsters treated with DMBA not only completely prevented the tumor formation but also restored thestatus of the above mentioned biomarkers. The present study thus demonstrates the chemopreventive potentialof andrographolide in DMBA-induced hamster buccal pouch carcinogenesis, which is probably due to itsantioxidant potential as well as modulating effect on xenobiotic metabolising enzymes during DMBA-inducedoral carcinogenesis.