胰腺癌患者血清肿瘤标志物的检测及其临床意义

 目的　观察胰腺癌患者血清肿瘤标志物的表达，分析其对胰腺癌诊断与预后判断的价值。方法　采用化学发光法检测95例胰腺癌患者AFP、CEA、CA199、CA125和酶联免疫吸附方法检测CA242，并与80例其他系统恶性肿瘤患者和65例良性疾病患者作比较，同时对不同TNM分期的胰腺癌的五个指标比较。结果　5种肿瘤标志物中CA199、CA125、CA242对胰腺癌的诊断有较高价值，其中CA199价值最高，灵敏度和特异度分别为76.2 %和74.8 %。CA199、CA242、CA125随着胰腺癌的病程进展而逐步升高。结论　血清 CA199、C242和 CA125的检测对胰腺癌的诊断和判断预后有价值。     

Molecular markers for renal cell carcinoma: impact on diagnosis and treatment

Molecular tumor markers are used to aid the differential diagnosis of renal cell carcinoma and to monitor disease progression and recurrence. They may also provide prognostic information and help in the design of therapeutic regimens. So far, no satisfactory markers are available for the diagnosis of renal cell carcinoma. Many markers have been evaluated for their potential use as prognostic factors. Some are promising, yet need vigorous clinical trials to validate. Genetic changes detected by molecular and cytogenetic methods provide markers specific for renal cell carcinoma. High-throughput DNA and tissue microarray techniques promise to revolutionize the discovery and validation of novel molecular markers.     

PDGFRβ expression in tumor stroma of pancreatic adenocarcinoma as a reliable prognostic marker

Pancreatic adenocarcinoma is a lethal disease that often develops a desmoplastic reaction in tumor stroma. In general, desmoplasia is thought to promote tumor growth. However, its molecular pathology and prognostic potential have not been fully investigated. Here, we investigate 26 cases of pancreatic ductal adenocarcinoma and examine the clinicopathological association between survival and expression levels of several molecular markers for stromal cells. These include alpha-smooth muscle actin (SMA) and platelet-derived growth factor (PDGF) receptor β (PDGFRβ). Both are markers of activated fibroblasts or pancreatic stellate cells (PSCs) that play an important role in desmoplasia. The staining patterns of both molecular markers were not uniform, so we categorized them into 3 grades (high, middle, and low) according to intensity. Interestingly, Kaplan-Meier analysis revealed that higher expression of PDGFRβ matched shorter prognosis (p?=?0.0287, log-rank test) as well as lymphatic invasion and lymph node metastasis, whereas SMA did not (p?=?0.6122). Our results suggest the prognostic potential of cancer stroma via PDGF-B signaling. Regulation of PDGF-B-associated signaling crosstalk between cancer cells and stroma cells, therefore, may indicate a possible therapeutic target for desmoplastic malignant tumors such as pancreatic adenocarcinoma.     

Comparative analysis of K-ras point mutation,telomerase activity,and p53 overexpression in pancreatic tumours

K-ras point mutation, p53 over-expression, and telomerase activity have been proposed as molecular markers for clinical diagnosis of pancreatic carcinoma. To evaluate the clinical usefulness of these markers, we performed comparative analysis in 61 resected pancreatic samples including 15 intraductal papillary-mucinous tumours (IPMTs), 4 mucinous cystic tumours, 37 ductal adenocarcinomas, and five chronic pancreatitis samples. K-ras point mutation, telomerase activity, and p53 overexpression were analyzed using mutant allele specific amplification, the telomeric repeat amplification protocol, and immunohistochemical staining, respectively. In malignant tumours, K-ras mutation, telomerase activity, and p53 overexpression were detectable in 76, 91, and 46%, respectively, while in benign tumours, these alterations were detectable in 38, 0, and 0%, respectively. Among 15 IPMTs, K-ras mutation was detectable in 4 (80%) of 5 IPMT-adenomas, 4 (80%) of 5 IPMT-carcinomas and 2 (66%) of 3 papillary-mucinous carcinomas, which are invasive carcinomas derived from IPMTs. Telomerase activity was not detectable in IPMT-adenomas, but was detected in all 5 IPMT-carcinomas and 3 papillary-mucinous carcinomas. p53 overexpression was not detected in IPMTs, but was detected in 2 (66%) of 3 papillary-mucinous carcinomas, indicating that telomerase is likely to be activated concomitant with carcinogenesis. These results suggest that telomerase activity is the most useful as a differential diagnostic marker between malignant and benign pancreatic tumours.     

Inhibition of pancreatic carcinoma growth by adenovirus-mediated human interleukin-24 expression in animal model

Interleukin-24 (IL-24) has been shown to be a tumor-suppressor gene and the protein product found to be constitutively expressed by melanocytes, nerve cells, and some primary melanomas. The potential effect of adenovirus (AdV)-mediated IL-24 gene therapy was explored on human pancreatic carcinoma by using a pancreatic carcinoma cell line, patu8988. A recombinant adenovirus, AdVGFP/IL-24, expressing the marker, green fluorescent protein (GFP), and the tumor-suppressor gene, IL-24, was constructed. AdVGFP/IL-24 treatment of pancreatic carcinoma cells in vitro significantly induced pancreatic carcinoma cell cytotoxicity and apoptosis, compared with AdVGFP without IL-24 expression. In nude mice bearing patu8988 tumors, intratumoral injections of AdVGFP/IL-24 significantly inhibited pancreatic carcinoma growth. In addition, the molecular mechanism of tumor suppression was elucidated by downregulating the expression of vascular endothelial growth factor, CD34, and Bcl-2, as well as inhibiting tumor angiogenesis. Therefore, AdVGFP/IL-24 has the potential to serve as a novel tool for pancreatic carcinoma gene therapy.     

The MUC gene family: Their role in diagnosis and early detection of pancreatic cancer

The early diagnosis of pancreatic cancer, as well as distinguishing between chronic pancreatitis and malignant pancreatic disease, remains still a clinical problem. Presently, there is no specific tumor marker for diagnosing pancreatic cancer. Mucin-associated marker like CA 19-9 are the most widely available pancreatic cancer tumor marker, but its value as a screening marker is limited by its reduced specificity.Mucins (MUCs) are heavily glycosylated, high molecular weight glycoproteins with an aberrant expression profile in various malignancies.This review considers briefly the potential use of the mucin expression pattern in diagnosis of pancreatic neoplasm. The overview will point out the present knowledge about changes in the mucin gene expression in pancreatic intraepithelial neoplasia (PanINs) as precursor lesions and in pancreatic adenocarcinoma, compared to normal pancreas and chronic pancreatitis and the potential role for differentiating chronic pancreatitis from pancreatic cancer.Furthermore, the potential use of MUCs in the diagnosis and differentiation of intraductal papillary-mucinous neoplasm's (IPMNs) will be discussed.     

Endocrine tumors of the pancreas

PURPOSE OF REVIEW: Neoplasms of the endocrine pancreas, commonly referenced as pancreatic islet cell tumors, are rare, often well differentiated endocrine neoplasms, whose biology remains poorly characterized. This article reviews the current clinical management of pancreatic islet cell tumors and describes the molecular events that have been studied to guide future therapies of these peculiar neoplasms. RECENT FINDINGS: While some islet cell tumors arise in association with the MEN-1 syndrome, the majority of these neoplasms are sporadic lesions whose underlying genetic and molecular events remain largely unknown. Recent work has identified changes in gene expression occurring in metastatic and non-metastatic islet cell tumors, which appear to correlate with the occurrence of lymph node and liver metastases. Epigenetic alterations of select tumor suppressor genes may influence patient survival, and the presence of gene promoter methylation may be used as a prognostic marker system. In addition, multiple molecular alterations, including changes in expression of cellular proteins with migratory, cell cycle or angiogenic functions, have been demonstrated to influence islet cell tumor growth, invasion and metastatic spread. SUMMARY: Understanding the molecular events underlying the biology of pancreatic islet cell tumors will aid the development of accurate prognostic markers and will guide improved therapeutic modalities in the future.     

Expression of epidermal and transforming growth factors in pancreatic cancer

Pancreatic cancer continues to be a major clinical problem and little is known of the various cellular and molecular events associated with this malignancy. Growth factors and their receptors have important functions in the process of tumor progression. We have examined by immunocytochemistry, the expression of epidermal growth factor (EGF), its receptor (EGFR) and the transforming growth factors alpha and beta (TGF alpha and beta) in various grades of pancreatic adenocarcinoma. Expression of the growth factors was compared to their distribution in apparently normal pancreas and chronic pancreatitis. EGF, TGF alpha and TGF beta was expressed in normal pancreatic tissue while the expression of EGFR was slight and restricted. In chronic pancreatitis, this expression of EGFR increased and was found to be moderate in intensity. Expression of EGF, TGF alpha and TGF beta was similar to that seen in normal pancreas. Moderate to intense expression of EGF and TGF alpha was evident in all grades of pancreatic cancer. Expression of EGFR was intense in all these lesions. However, the most significant finding was the absence of TGF beta in all pancreatic cancer lesions. These results may have significant implications for pancreatic tumor progression. EGF and TGF alpha are growth promoters influencing the expression of EGFR. TGF beta, on the other hand exerts an anti-proliferative effect and favours differentiation. It therefore appears that the balance between EGF and TGF alpha on the one hand and TGF beta on the other may be critical in the process of tumor progression, especially if one considers chronic pancreatitis as a pre-malignant condition and the growth factor expression associated with it.     

Small cell undifferentiated carcinoma of the pancreas. Report of a patient with tumor marker studies.

BACKGROUND. Small cell undifferentiated carcinoma of the pancreas is a rare type of pancreatic neoplasm. METHODS. The authors report the clinical and pathologic aspects of a patient with this malignant lesion and an extensive serologic and immunohistochemical survey of potential ectopically produced hormones or tumor markers. RESULTS. Neuron-specific enolase (NSE) emerged as a tumor marker. CONCLUSIONS. NSE could be valuable in the diagnosis and management of other patients with this rare disease.     

Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation

Bombesin-like peptides such as gastrin-releasing peptide (GRP) have been shown to play a role in cancer as autocrine growth factors that stimulate tumor growth through specific receptors. To search for potential clinical indications for GRP analogues, it is important to identify human tumor types expressing sufficient amounts of the respective receptors. In the present study, we have evaluated the expression of GRP receptors in human nonneoplastic and neoplastic prostate tissues using in vitro receptor autoradiography on tissue sections with 125I-Tyr4-bombesin as radio-ligand. GRP receptors were detected, often in high density, in 30 of 30 invasive prostatic carcinomas and also in 26 of 26 cases of prostatic intraepithelial proliferative lesions, corresponding mostly to prostatic intraepithelial neoplasias. Well-differentiated carcinomas had a higher receptor density than poorly differentiated ones. Bone metastases of androgen-independent prostate cancers were GRP receptor-positive in 4 of 7 cases. Conversely, GRP receptors were identified in only a few hyperplastic prostates and were localized in very low density in glandular tissue and, focally, in some stromal tissue. In all of the cases, the receptors corresponded to the GRP receptor subtype of bombesin receptors, having high affinity for GRP and bombesin and lower affinity for neuromedin B. These data demonstrate a massive GRP receptor overexpression in prostate tissues that are neoplastically transformed or, like prostatic intraepithelial neoplasias, are in the process of malignant transformation. GRP receptors may be markers for early molecular events in prostate carcinogenesis and useful in differentiating prostate hyperplasia from prostate neoplasia Such data may not only be of biological significance but may also provide a molecular basis for potential clinical applications such as GRP-receptor scintigraphy for early tumor diagnosis, radiotherapy with radiolabeled bombesin-like peptide analogues, and chemotherapy with cytotoxic bombesin analogues.     

Influences of the lysosomal associated membrane proteins (Lamp-1, Lamp-2) and Mac-2 binding protein (Mac-2-BP) on the prognosis of pancreatic carcinoma

BACKGROUND: Lamps and Mac-2-BP are ligands of galectin-3, and they were suggested to influence tumor proliferation and metastasis formation. The authors studied the expression of Lamp-1, Lamp-2, and Mac-2-BP in pancreatic carcinoma and evaluated their influence on patient prognosis. METHODS: Northern blot analysis, in situ hybridization, and immunohistochemistry were performed in 12 normal and 28 pancreatic carcinoma tissue samples and in pancreatic carcinoma cell lines. The molecular findings in the tumor samples were correlated with the prognosis and histopathologic tumor characteristics. In addition, in Lamp-1 transfected CAPAN-1 pancreatic carcinoma cells, cell proliferation was analyzed. RESULTS: Lamp-1, Lamp-2, and Mac-2-BP were overexpressed in 61% (1.6-fold increase, not significant), 71% (3.0-fold increase, P < 0.01), and 93% (5.6-fold increase, P < 0.01) of the pancreatic carcinoma samples. Lamp-1 and Lamp-2 immunoreactivity was present at the luminal side of the ductal carcinoma cells whereas Mac-2-BP immunoreactivity was diffusely spread over the whole cytoplasm and the nucleolus of ductal carcinoma cells. Correlation of the molecular data with clinical patient parameters revealed that patients whose tumors exhibited high Lamp-1 mRNA expression lived significantly longer (median, 17 months) after tumor resection than patients whose tumors exhibited low to moderate Lamp-1 mRNA levels (median, 8 months; P < 0.02). No relation between Lamp-2 and Mac-2-BP mRNA expression and any of the histopathologic parameters was found. Lamp-1 transfected CAPAN-1 cells showed decreased cell growth compared with the nontransfected cells. CONCLUSIONS: Lamp-1 might influence local tumor progression rather than the formation of tumor metastasis in pancreatic carcinoma, whereas Mac-2-BP and Lamp-2 seem to have little influence on these parameters in pancreatic carcinoma.     

胰腺癌患者血浆溶血磷脂酸的临床意义

目的:检测胰腺癌患者血浆溶血磷脂酸(lysphosphaticlic acid,LPA)的水平,评价LPA在胰腺癌诊治中的临床意义。方法:采用定磷法检测2006年6月至2010年10月南京第一医院收治的胰腺癌患者50例、胰腺良性疾病患者32例及健康志愿者36人的血浆LPA水平,同时测定血清CA19-9、AFP和CEA的水平;免疫组化法检测胰腺癌组织及癌旁胰腺组织LPA2受体的表达。分析血浆LPA水平与胰腺癌临床病理特征的关系。结果:胰腺癌患者血浆LPA水平明显高于胰腺良性疾病患者和健康志愿者[(4.10±2.03)vs(3.28±1.26)、(2.27±1.02)μmol/L,P<0.05],胰腺癌患者血浆LPA水平和血清CA19-9水平密切相关(r=0.9070,P<0.01)。胰腺癌组织LPA2受体表达阳性率显著高于癌旁正常胰腺组织(88%vs 4%,P<0.05)。血浆LPA水平的升高与胰腺癌浸润和淋巴结转移等相关。结论:血浆LPA检测为胰腺癌诊断和预后判断增加了一项潜在的评价指标。     

The expression and functions of microRNAs in pancreatic adenocarcinoma and hepatocellular carcinoma

Pancreatic adenocarcinoma and hepatocellular carcinoma are devastating human malignancies that are characterized by poor prognosis, late onset, and a lack of known biomarkers. New diagnostic and therapeutic molecular targets are desperately needed to develop novel and effective treatment strategies. MicroRNAs (miRNAs) are an emerging class of molecules with roles in various cellular processes, including growth, survival, and apoptosis. Most importantly, aberrant expression of miRNAs has been implicated in cancer pathogenesis. miRNA expression profiles of pancreatic adenocarcinoma and hepatocellular carcinoma indicate selective overexpression of oncogenic miRNAs and down-regulation of tumor suppressive miRNAs in these cancers. This review summarizes results from key studies conducted to characterize the miRNA expression profiles of pancreatic adenocarcinoma and hepatocellular carcinoma and describes the potential mechanisms by which some oncogenic or tumor suppressive miRNAs act. Furthermore, this review outlines novel therapeutic strategies for targeting miRNAs.     

Adiponectin,Leptin, and Insulin-Pathway Receptors as Endometrial Cancer Subtyping Markers

Developing a system of molecular subtyping for endometrial tumors might improve insight into disease etiology and clinical prediction of patient outcomes. High body mass index (BMI) has been implicated in development of endometrial cancer through hormonal pathways and might influence tumor expression of biomarkers involved in BMI-sensitive pathways. We evaluated whether endometrial tumor expression of 7 markers from BMI-sensitive pathways of insulin resistance could effectively characterize molecular subtypes: adiponectin receptor 1, adiponectin receptor 2, leptin receptor, insulin receptor (beta subunit), insulin receptor substrate 1, insulin-like growth factor 1 receptor, and insulin-like growth factor 2 receptor. Using endometrial carcinoma tissue specimens from a case-only prospective sample of 360 women from the Nurses’ Health Study, we scored categorical immunohistochemical measurements of protein expression for each marker. Logistic regression was used to estimate associations between endometrial cancer risk factors, especially BMI, and tumor marker expression. Proportional hazard modeling was performed to estimate associations between marker expression and time to all-cause mortality as well as time to endometrial cancer-specific mortality. No association was observed between BMI and tumor expression of any marker. No marker was associated with time to either all-cause mortality or endometrial cancer-specific mortality in models with or without standard clinical predictors of patient mortality (tumor stage, grade, and histologic type). It did not appear that any of the markers evaluated here could be used effectively to define molecular subtypes of endometrial cancer.     

Molecular alterations in the pathogenesis of endometrial adenocarcinoma. Therapeutic implications

Summary Molecular genetic evidence indicates that endometrial carcinoma likely develops as the result of a multistep process of oncogene activation and tumor suppressor gene inactivation. These molecular alterations appear to be specific for Type I (endometrioid) and Type II (non endometrioid) cancers. Type I cancers are characterized by mutation of PTEN, KRAS2, defects in DNA mismatch repair, as evidenced by the microsatellite instability phenotype, and a near diploid karyotype. Type II cancers often contain mutations of TP53 and Her-2/neu and are usually nondiploid. The clinical value of many of these molecular markers is now being tested and it may help to refine diagnosis and establish an accurate prognosis. Furthermore, some of these tumor biomarkers constitute the targets for emerging therapies. Transtuzumab against Her-2/neu and bevacizumab against VEGF overexpressing carcinomas are among the promising novel treatments. Additional translational research is needed to identify molecular and genetic alterations with potential for therapeutic interventions. Supported by an unrestricted educational grant by Bristol-Myers Squibb.     

The neurotrophin-trk receptor axes are critical for the growth and progression of human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice.

PURPOSE: Aberrant expression of trk receptor kinases and enhanced expression of various neurotrophins (NTs) have been implicated in the development and progression of human prostatic carcinoma and pancreatic ductal adenocarcinoma. We examined the antitumor efficacy of administration of NT neutralizing antibodies on the growth of established human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice. EXPERIMENTAL DESIGN: In initial studies, tumor-bearing nude mice were treated with a mixture of NT antibodies [100 microg each of anti-nerve growth factor (NGF), anti-brain-derived neurotrophic factor, anti-NT-3, and anti-NT-4/5] or normal rabbit IgG (400 microg) intratumorally and peritumorally three times/week over a 15-day dosing period. In subsequent studies, tumor-bearing nude mice were treated with individual NT antibodies (100 microg), affinity-purified anti-NGF (0.1, 1.0, or 10.0 microg), or normal rabbit IgG (100 microg) using the same dosing schedule. RESULTS: Treatment with the antibody mixture inhibited significantly the growth of TSU-Pr1 and AsPC-1 xenografts as compared with IgG-treated controls (maximal inhibition of 53 and 53%, respectively), whereas this treatment caused significant regression in PC-3 xenografts. Treatment of TSU-Pr1 xenografts with either anti-NGF or anti-NT-3 resulted in maximal tumor growth inhibition of 67 and 64%, respectively, whereas anti-brain-derived neurotrophic factor and anti-NT-4/5 did not inhibit tumor growth in this tumor model. Administration of various concentrations (0.1, 1.0, or 10.0 microg) of affinity-purified anti-NGF resulted in maximal TSU-Pr1 tumor growth inhibition of 49, 62, and 66%, respectively. CONCLUSIONS: These data add further support for the therapeutic potential of disrupting trk-signaling events in select types of nonneuronal human cancers, specifically prostatic and pancreatic carcinomas.     

乙酰肝素酶和MMP-9 在胰腺癌中的表达及临床意义*

目的:检测乙酰肝素酶（heparanase,HPA ）和基质金属蛋白酶-9（matrix metalloproteinase-9,MMP-9）在胰腺癌、慢性胰腺炎、正常胰腺组织中的表达及相互关系,分析其与浸润转移的关系。方法:应用免疫组化SP法检测92例胰腺癌、24例慢性胰腺炎和10例正常胰腺组织中HPA 、MMP-9 的表达水平,分析两者的表达与临床病理指标的关系,建立Spearman 等级相关分析。结果:HPA 在胰腺癌中表达明显高于慢性胰腺炎和正常胰腺组织（P<0.05）,HPA 阳性表达与周围组织浸润、淋巴结转移呈正相关（P<0.05）,与性别、年龄及组织学分级无统计学相关（P>0.05）;胰腺癌组织中MMP-9 表达明显高于慢性胰腺炎和正常胰腺组织（P<0.05）,且MMP-9 阳性表达与周围组织浸润、远处转移正相关（P<0.05）,与性别、年龄、组织学分级无统计学相关（P>0.05）。HPA 与MMP-9 有较高的共同阳性表达率。HPA 和MMP-9 表达呈正相关（P<0.05）,其共同表达率与肿瘤对周围脏器浸润和淋巴结转移有相关（P<0.05）。 多因素分析显示HPA 和MMP-9 均非影响预后的独立因素。结论:HPA 、MMP-9 在胰腺癌组织中的表达可能与胰腺癌浸润、转移相关,可作为新的胰腺癌标记物用于联合检测,具有重要的临床意义。且MMP-9 可能上调HPA 表达水平,促进HPA 介导的肿瘤浸润转移。