Strong expression of chemokine receptor CXCR4 by pancreatic cancer correlates with advanced disease

Certain chemokines have been proposed to distinctly contribute to tumor growth, dissemination and local immune escape. Expression of the chemokine receptor CXCR4 has been linked to tumor progression in diverse tumor entities. The aim of this study was to evaluate if the expression of CXCR4 influences progression of human pancreatic cancer. CXCR4 expression of pancreatic cancer was retrospectively assessed by immunohistochemistry in 103 patients with pancreatic cancer. Intensity of CXCR4 expression was correlated with both tumor and patient characteristics. Human pancreatic cancer revealed variable intensities of CXCR4 expression. Strong CXCR4 expression was significantly associated with advanced UICC stages (P=0.03) and revealed a trend for hematogenous metastasis (P=0.09) and progressed local tumor stages (P=0.15). In summary, strong expression of CXCR4 was significantly associated with advanced pancreatic cancer.     

Epithelial MMP-2 expression correlates with worse prognosis in pancreatic cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) degrade extracellular matrix and are involved in tumor invasion and metastasis in various cancers. In pancreatic cancer, MMP-2 expression is upregulated and correlates with tumor recurrence. The aim of this study was to evaluate the prognostic significance of MMP-2 in pancreatic ductal adenocarcinoma. METHODS: MMP-2 expression was assessed by immunohistochemistry in 127 patients operated on at Helsinki University Hospital from 1974 to 1998, with expression interpreted separately in epithelial and stromal samples. RESULTS: Epithelial MMP-2 expression was strong in 5%, moderate in 20%, weak in 25% and negative in 50% of the tumors, with high epithelial MMP-2 expression significantly associated in univariate survival analysis with advanced stage, poor grade and poor survival. Stromal MMP-2 expression was strong in 0%, moderate in 14%, weak in 70% and negative in 16% of the cases, and did not significantly correlate with patient survival. CONCLUSION: Epithelial MMP-2 correlates with advanced tumor stage and grade, but is not an independent predictor of survival.     

Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer.

PURPOSE: The reasons for the high frequency of perineural invasion and the presence of pain in pancreatic cancer are still not clear. Nerve growth factor (NGF) and its high-affinity receptor TrkA are involved in stimulating epithelial cancer cell growth and perineural invasion, as well as in pain generation in chronic benign disorders. PATIENTS AND METHODS: NGF and TrkA were examined by Northern blot analysis, in situ hybridization, and immunohistochemistry in 27 normal and 37 pancreatic cancer tissue samples. The molecular findings were correlated with the degree of perineural invasion, pain, and histopathologic tumor characteristics. RESULTS: Northern blot analysis indicated that NGF and TrkA mRNA levels were increased 2.7-fold and 5.6-fold, respectively (P <.05 and P <.05), in pancreatic cancer tissues compared with the normal pancreas tissue. As shown by in situ hybridization and immunohistochemistry, NGF was strongly present in the cytoplasm of pancreatic cancer cells. TrkA was intensely present in the perineurium of pancreatic nerves but not in the cancer cells. There was no difference in NGF and TrkA expression between early (stages I and II) and advanced (stage III) tumor stages and between well-/moderately differentiated (grades 1 and 2) and poorly differentiated (grade 3) tumors. However, tumors with high NGF/TrkA expression levels exhibited more frequent perineural invasion (P <.01). Furthermore, increased NGF/TrkA expression levels were associated with a higher degree of pain (P <. 01). CONCLUSION: Enhanced expression of the NGF/TrkA system may influence perineural invasion and may contribute to the pain syndrome in human pancreatic cancer.     

结直肠癌转移潜能的预测与癌转移相关基因的表达

目的 研究结直肠癌活检黏膜癌转移相关基因的表达与淋巴结转移的关系,探讨它们在预测结直肠癌淋巴结转移的应用价值。方法 用免疫组化S-P法检测94例结直肠癌活检黏膜CD44V6、E-cadherin、EGFR、VEGF、nm23-H1、Fas、FasL、p53、Cathepsin-B、Cathepsin-D、C-erbB-2的表达,分析这些指标与结直肠癌淋巴结转移的关系。结果 11项指标中仅CD44V6、EGFR、VEGF的阳性率和nm23-H1的缺失率与淋巴结转移有关,但它们在预测淋巴结转移方面的敏感性和特异性较低。CD44V6(+)EGFR(+)、EGFR(+)nm23-H1(-)、VEGF(+)nm23-H1(-)、CD44V6(+)Cath-D(+)、CD44V6(+)Fas(-)、VEGF(+)Fas(-)、EGFR(+)Fas(-)和Cath-D(+)Fas(-)等8对两因素组合与淋巴结转移有关。两因素组合可提高预测淋巴结转移的特异性,但敏感性明显降低。结论 活检癌黏膜CD44V6、EGFR、VEGF和nm23-H1等癌转移相关基因的表达与结直肠癌转移潜能有关。但它们预测淋巴结转移的敏感性和(或)特异性较低,临床术前应用易造成较高的漏诊率和误诊率,应用价值不大。     

High expression of TROP2 correlates with poor prognosis in pancreatic cancer

Pancreatic cancer is one of the most devastating human malignancies. Despite considerable research efforts, it remains resistant to almost all available treatment regimens. The human trophoblast cell-surface antigen, TROP2, was found to be strongly expressed in a variety of human epithelial cancers, correlating with aggressiveness and poor prognosis. TROP2 antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumour tissue samples from a series (n=197) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated using Kaplan-Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 109 (55%) of 197 pancreatic cancer patients and was significantly associated with decreased overall survival (P<0.01). By univariate analysis, TROP2 overexpression was found to correlate with the presence of lymph node metastasis (P=0.04) and tumour grade (P=0.01). Furthermore, in the subgroup of patients treated surgically with curative intent, TROP2 overexpression significantly correlated with poor progression-free survival (P<0.01). Multivariate analyses revealed TROP2 to be an independent prognosticator. These findings suggest for the first time that TROP2 could be a novel prognostic biomarker for pancreatic cancer. Targeting TROP2 might be a useful treatment approach for patients with pancreatic cancer overexpressing this cell-surface marker.     

黏蛋白4在胰腺上皮内瘤变和胰腺癌中的表达差异性分析

目的 探讨黏蛋白4（MUC4）在胰腺上皮内瘤变（PanINs）和胰腺导管腺癌（PDAC）中的表达及临床意义。方法 收集2009年3月1日至2011年12月31日第二军医大学附属长征医院的胰腺组织蜡块标本共85例。采用免疫组化SP法检测MUC4在48例正常胰腺导管（NP）、17例PanINs及20例PDAC组织中的表达情况。分析MUC4的表达与PDAC临床病理特征及预后的关系。结果 MUC4在NP组织中不表达;随着胰腺组织异型程度的增加,MUC4的表达逐渐增强;MUC4在NP、PanIN-1、PanIN-2、PanIN-3及PDAC组织中的阳性表达率分别为0、17.4%、52.6%、84.6%和90.0%;免疫组化评分分别为0、1.30±089、2.58±1.76、4.54±1.64和7.68±2.34,组间比较差异有统计学意义（P＜0.001）。MUC4在PDAC组织中的表达与神经浸润（P=0.028）、淋巴结转移（P=0.020）和CA19-9（P=0.028）有关。20例PDAC患者的中位总生存时间为17.0个月（95%CI：14.809～19.191个月）;MUC4高表达者（免疫组化评分≥8.8分）为13.0个月（95%CI：7.456～18.544个月）,MUC4低表达者（免疫组化评分＜8.8分）为20.0个月（95%CI：15.521～24.479个月）,差异有统计学意义（P=0.003）。结论 MUC4可能参与了PDAC的发生、发展,其表达升高可能是PDAC演进的早期事件,MUC4高表达可能对PDAC的浸润和转移均有影响并提示预后不良。     

BCL2 expression correlates with metastatic potential in pancreatic cancer cell lines

BACKGROUND: Programmed cell death (termed apoptosis) regulates normal tissue homeostasis. Loss of local paracrine signals and intercellular adhesion molecules are potent inducers of apoptosis and thereby eliminate normal cells that may have escaped beyond the confines of the local organ environment. Dysregulation in the expression of the BCL2 gene family, the prototypic regulators of apoptosis, is a common occurrence in cancer and imparts resistance to standard triggers of apoptosis. Therefore, the authors sought to examine whether abnormal BCL2 gene family expression correlated with resistance to apoptosis and increased metastatic potential in pancreatic carcinoma. METHODS: The authors examined BCL2 expression and apoptotic sensitivity in three panels of human pancreatic cancer cell lines that possess varying metastatic potential. Stable transfectants were generated that overexpress BCL2. These transfectants were then analyzed for differences in metastasis formation in athymic mice. RESULTS: Among the isogenic panels of pancreatic cancer cell lines, BCL2 expression levels correlated with metastatic potential. Highly metastatic variants of each family of cell lines were more resistant to induction of apoptosis. Finally, using the BCL2 transfectant in a xenograft model, elevated BCL2 expression led to a higher incidence of metastases. CONCLUSIONS: The authors conclude that increased BCL2 expression correlates with apoptotic resistance and metastatic potential; dysregulation of BCL2 expression may be involved in the metastatic progression of pancreatic carcinoma.     

Circulating tumor DNA correlates with tumor burden and predicts outcome in pancreatic cancer irrespective of tumor stage

IntroductionCirculating tumor DNA (ctDNA) represents a promising tool for diagnosis, prognosis and treatment monitoring of several malignancies. Its association with tumor burden in pancreatic ductal cancer (PDAC), especially in localized disease, is not fully explored yet. We aimed to investigate the association of pretherapeutic ctDNA levels in localized and metastatic PDAC with tumor volume and clinical outcomes.Material and methodsLiquid biopsy for ctDNA detection was prospectively obtained from patients with localized or disseminated PDAC prior to either resection or systemic treatment. Detection rates and levels of ctDNA (digital droplet PCR) were correlated to tumor volume, relapse rate and survival.Results60 patients with localized and 47 patients with metastatic PDAC were included. ctDNA was detected in 10% of localized and 57.4% of metastasized PDAC samples. In localized disease, ctDNA detection significantly correlated with the numbers of involved locoregional lymph nodes (p = 0.030). Primary tumor volume did not correlate with ctDNA levels in neither localized (p = 0.573) nor metastasized disease (p = 0.878). In disseminated disease, ctDNA levels correlated with total tumor volume (p = 0.026) and especially with liver metastases volume (p = 0.004), but not with other metastases. Detection of pretherapeutic ctDNA was associated with shorter DFS in localized (3.3 vs. 18.1 months, p = 0.000), whereas ctDNA levels were associated with worse survival in metastatic PDAC (5.7 vs. 7.8 months, p = 0.036).ConclusionctDNA positivity indicates major nodal involvement or even presence of undetected distant metastases associated with early recurrence in localized PDAC. Moreover, it predicts worse clinical outcome in both localized and metastatic disease.     

Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage.

The tumor suppressor gene PTEN/MMAC-1/TEP-1 (referred to hereafter as PTEN) maps to chromosome 10q23 and encodes a dual specificity phosphatase. The PTEN protein negatively regulates cell migration and cell survival and induces a G1 cell cycle block via negative regulation of the phosphatidylinositol 3'-kinase/protein kinase B/Akt signaling pathway. PTEN is frequently mutated or deleted in both prostate cancer cell lines and primary prostate cancers. A murine polyclonal antiserum was raised against a glutathione S-transferase fusion polypeptide of the COOH terninus of PTEN. Archival paraffin tissue sections from 109 cases of resected prostate cancer were immunostained with the antiserum, using DU145 and PC-3 cells as positive and negative controls, respectively. PTEN expression was seen in the secretory cells. Cases were considered positive when granular cytoplasmic staining was seen in all tumor cells, mixed when areas of both positive and negative tumor cell clones were seen, and negative when adjacent benign prostate tissue but not tumor tissue showed positive staining. Seventeen cases (15.6%) of prostate cancer were positive, 70 cases (64.2%) were mixed, and 22 cases (20.2%) were negative. Total absence of PTEN expression correlated with the Gleason score (P = 0.0081) and correlated more significantly with a Gleason score of 7 or higher (P = 0.0004) and with advanced pathological stage (American Joint Committee on Cancer stages T3b and T4; P = 0.0078). Thus, loss of PTEN protein is correlated with pathological markers of poor prognosis in prostate cancer.     

伴颈部淋巴结转移的甲状腺乳头状癌的基因差异表达

背景与目的：甲状腺乳头状癌是预后较好的一种恶性肿瘤，颈部淋巴结转移是其主要的转移方式。近年来迅猛发展起来的基因芯片技术是研究肿瘤生物学行为的一种快速、高效的方法。本研究拟比较初治有颈部淋巴结转移（cN1）的甲状腺乳头状癌组织与正常甲状腺组织的基因差异表达，筛选甲状腺乳头状癌的转移相关基因。方法：分别用Cy3和Cy5两种荧光染料标记两组组织的总mRNA，与含有14112个基因位点的芯片进行杂交。通过对荧光信号的扫描、分析，筛选两组差异表达的基因。结果：共有1212个基因位点在两组间出现差异表达，占总基因点位数的8．71％。其中22个位点呈显著差异表达（上调或下调8倍以上）。在显著下调的6个位点中，有2个位点代表同一个基因序列（NM-001920）——decorin蛋白的mRNA序列。结论：基因芯片是研究疾病发生发展过程中基因表达改变的有效方法之一。PTC的发生发展（包括颈部淋巴结转移）涉及众多的基因参与。Decorin蛋白可能在甲状腺乳头状癌颈部淋巴结转移中发挥重要作用。     

Reduced expression of Raf kinase inhibitor protein correlates with poor prognosis in pancreatic cancer

Aim

Raf kinase inhibitory protein (RKIP) is an inhibitor of the Raf/MEK/MAP kinase signaling cascade and a suppressor of cancer metastasis. But its function in pancreatic cancer was not yet clarified completely. The aim of this study was to investigate the involvement of RKIP in pancreatic cancer.

Methods

RKIP expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumor tissue samples from a series (n?=?99) of consecutive patients with pancreatic cancer. Survival was calculated using Kaplan?CMeier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model.

Results

RKIP expression was high in normal pancreatic epithelium and retained to varying degrees in pancreatic cancer tissues. However, in tumor tissues with lymph node metastasis (P?=?0.008) and high UICC stage (P?=?0.006), RKIP expression was highly significantly reduced or lost. Furthermore, the reduced expression of RKIP significantly correlated with both poor overall and disease-free survival (P?=?0.008 and 0.01, respectively). Multivariate analyses revealed RKIP to be an independent prognosticator.

Conclusion

These findings suggest that RKIP could be a promising marker for predicting a better prognosis in pancreatic cancer.     

Differential expression of cancer testis genes in histological subtypes of non-Hodgkin's lymphomas.

PURPOSE: The purpose of this study was to determine the potentialof cancer testis (CT) antigens as vaccines for non-Hodgkin's lymphomas (NHLs). EXPERIMENTAL DESIGN: Ninety-three specimens of NHLs were analyzed for their composite expression of eight CT genes (MAGE-3, MAGE-4, CT-7, HOM-MEL-40/SSX-2, SSX-1, SSX-4, HOM-TES-14/SCP-1, and HOM-TES-85). Thirty-nine of these specimens were also analyzed for their NY-ESO-1 expression. RESULTS: Only 1 of 7 cases of chronic lymphocytic leukemia expressed a CT gene (HOM-TES-14/SCP-1), and 10 follicular lymphomas were negative for all of the CT genes tested. In B-cell lymphomas, the most frequent expression of CT genes was observed in diffuse large-cell lymphomas (HOM-TES-14/SCP-1: 7 of 28; SSX-1: 5 of 28; CT-7: 2 of 28; and HOM-MEL-40/SSX-2 and HOM-TES-85: 1 of 28 positive cases). Only 1 of 8 Burkitt's and 1 of 7 lymphoblastic lymphomas expressed a CT gene (CT7 and HOM-TES-14/SCP-1, respectively). A majority (9 of 15) of T- NHLs (9 peripheral T-cell lymphomas, 2 lymphoblastic T-cell lymphomas, and 4 cases of AILD) expressed HOM-TES-14/SCP-1. CONCLUSIONS: HOM-TES-14/SCP-1, and to some degree SSX-1 and CT-7 might be candidates for lymphoma vaccine development. However, the identification of additional tumor-specific antigens with a frequent expression in lymphomas is warranted to allow for the development of widely applicable polyvalent lymphoma vaccines.     

Loss of hMLH1 expression correlates with improved survival in stage III-IV ovarian cancer patients

Pre-clinical data suggest a relationship between DNA MisMatch Repair (MMR) system failure, particularly the inactivation of genes hMLH1 and hMSH2, and resistance to drugs like cisplatin and carboplatin. We studied the correlation between loss of hMLH1 expression in tumour cells and clinical outcome in 38 patients with ovarian cancer, who underwent cisplatin-based chemotherapy. 19 patients (56%) showed loss of hMLH1 expression (Group A) while 15 patients (44%) showed normal hMLH1 expression (Group B). 4 patients were not evaluable for hMLH1 expression. The 2 groups of patients were similar for clinical characteristics, response to chemotherapy and time to progression. Group A patients showed a median survival of 55 months whereas Group B patients had a median survival of 12 months (P=0.014). Loss of hMLH1 expression was the only independent predictor of survival in the multivariate analysis. Our observations suggest a relationship between loss of hMLH1 and improved survival in advanced ovarian cancer.     

Differential expression of TRAIL-R3 and TRAIL-R4 in human pancreatic cancer

BACKGROUND: Pancreatic cancer is one of the most aggressive cancers, in part due to its insensitivity to most treatment modalities. This resistance towards cytotoxic therapy is thought to be caused--at least in part--by a general resistance of pancreatic cancer cells towards apoptosis. TRAIL-R3 and TRAIL-R4, which belong to the TRAIL receptor family, can inhibit TRAIL-induced apoptosis. PATIENTS AND METHODS: Seven normal pancreatic tissues and 7 pancreatic cancer tissues were analyzed using Northern blotting, Western blotting and immunohistochemistry. RESULTS: TRAIL-R3 mRNA and protein expression were generally weak in pancreatic cancers and normal pancreatic tissues. In contrast, TRAIL-R4 mRNA and protein were expressed at moderate to high levels in human pancreatic cancer tissues, but demonstrated weak to negative expression in the normal pancreas. CONCLUSION: TRAIL-R4 but not TRAIL-R3 levels were significantly different in pancreatic cancer in comparison to the normal pancreas. These findings give new insight into the resistance mechanisms of pancreatic cancer towards TRAIL-mediated apoptosis.