2024-03-29T00:56:48Z
https://journal.waocp.org/?_action=export&rf=summon&issue=3484
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Systemic Therapy for Locally Advanced and Metastatic Cholangiocarcinoma
Cholangiocarcinoma, the typical bile duct epithelium neoplasm, is most commonly reported in the Northeast ofThailand. Surgical intervention is the only possible curative treatment in the early stage of disease. Unfortunately,most patients are advanced at the time of diagnosis and not appropriate for curative surgical treatment. Theprognosis of advanced CCA is extremely poor and chemotherapy is the only approved treatment for this stage ofdisease. This article reviews the state-of-art chemotherapy for locally advanced or metastatic cholangiocarcinoma.
Antineoplastic agents
bile duct neoplasms
Liver neoplasms
systemic treatment
2012
12
01
3
6
https://journal.waocp.org/article_27139_e31d6eac4f4d2bede432bc54af251abd.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Genetic Polymorphism of Drug Metabolizing Enzymes inAssociation with Risk of Bile Duct Cancer
Cholangiocarcinoma (CCA) is the most common cancer in endemic areas of liver fluke infection. Althoughthe liver fluke is recognized as a carcinogenic agent in cholangiocarcinogenesis, other factors may play importantroles in bringing about the high prevalence of the cancer in populations of this region. Drug metabolizingenzymes (DME) are essential for detoxification of toxic and carcinogenic chemicals. Moreover, DME can play analternative role by activating chemicals to more toxic metabolites. The large variation of DME activity amongindividuals is partly due to polymorphism of the genes encoding enzymes. Defective or variant alleles of DMEgenes may modify the risk of cancer in those who are exposeed to carcinogenic agents. The focus in this reviewis on DME genes which have been reported to be associated with CCA risk. These include CYP1A2, arylamine-N-acetyltransferase-1 (NAT1) and NAT2, NADPH-quinone oxidorecutase-1 (NQO1), glutathione-S-transferaseM1 (GSTM1), GSTT1, GSTO1 and methylenetetrahydrofolate reductase (MTHFR). Mutant alleles which havebeen reportedly associated with an increased risk include CYP1A2*1F, GSTT1 null, GSTO1 and MTHFR 677C>T,whereas, slow NAT2 and NQO1*2 decrease risk and NAT1 variants and GSTM1 null have no effect. These genesmodify the risk of cancer potentially by interaction and exposure with certain environmental conditions, therebyaltering the metabolism of causative agents.
pharmacogenetics
drug metabolizing enzymes
cholangiocarcinoma
CYP1A2
Glutathione-S-transferase
2012
12
01
7
15
https://journal.waocp.org/article_27140_b8c96d0a2940ca4bff3ac3c9ed8d1287.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
State of Serum Markers for Detection of Cholangiocarcinoma
Difficulties in cholangiocarcinoma (CCA) management are largely due to the lack of specific biomarkers todiagnose CCA patients at an early stage. Most of CCA patients are diagnosed when the tumors have alreadyextensively invaded and/or metastasized, resulting in poor survival. Definite diagnosis for CCA is through ahistopathological study of e liver tissues, which is invasive to obtain the samples. The detection of CCA-associatedmarkers in patients’ sera seems to be a potential diagnostic approach, which is less invasive, inexpensive, anddoes not require a specialist to perform the diagnosis. To date, several serum markers, such as carcinoembryonicantigen, carbohydrate antigen (CA) 19-9, CA242, CCA-associated carbohydrate antigen, mucin glycoproteins,cytokines, etc., have been reported to be the potent diagnostic and prognostic markers for CCA. However, a singlemarker determination exhibits low sensitivity and specificity for diagnosis of CCA. Alternatively, multiple markeranalysis seems to have more optimistic prospects for improvement of diagnostic and prognostic determinationof CCA.
Tumor
Diagnosis
Prognosis
bile duct
Early Diagnosis
Blood
2012
12
01
17
27
https://journal.waocp.org/article_27141_c951b129186afc59e436fd0e97c612fd.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Autoimmunity and Cancer
The association between autoimmune diseases and cancer is to be considered one of the most well establishedand clinically challenging issues. Several mechanisms are shared in the pathogenesis of both autoimmune diseasesand cancer, they are thus direct candidates as causative factors, but direct proof is lacking, as in the case ofserum autoantibodies. Furthermore, accurate estimates of the risk of cancer in patients with newly diagnosedor long-standing autoimmune disease remain to be reported. The role of awareness bias and diagnosis latency,as well as of serum autoantibodies, epigenetics and genomic susceptibility, cannot be overlooked in this scenario.Finally, an indirect proof of associations is provided by the common autoimmune phenomena presenting asparaneoplastic. The present article will critically review the available evidence on the common mechanisms andepidemiology underlying the risk of cancer in patients with autoimmune disease.
autoimmunity
cancer
Genetic susceptibility
Epidemiology
2012
12
01
29
40
https://journal.waocp.org/article_27142_fe9db5509833cfd2470fecbdc768b8c7.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Epigenetic Aberrations in Cholangiocarcinoma: Potential Biomarkers and Promising Target for Novel Therapeutic Strategies
Cholangiocarcinoma (CCA) is a notoriously lethal malignancy arising from the biliary tract epithelium.While relatively rare, incidence rates have increased markedly worldwide in the past decade. Although definiterisk factors such as primary sclerosing cholangitis, liver fluke infestation, and hepatolithiasis have been welldocumented,the cause of CCA remains unknown for most cases. An importance of not only genetic alterations butalso epigenetic aberrations, including promoter hypermethylation and histone modifications, has been indicatedfor the processes of carcinogenesis and pathogenesis of CCA. This review focuses on epigenetic mechanismsinvolved in CCA genesis, with special emphasis on their applicability as potential biomarkers for diagnosis,prognosis and prediction as well as promising targets for novel therapeutic strategies.
Epigenetics
methylation
histone modifications
Biomarkers
cancer
2012
12
01
41
45
https://journal.waocp.org/article_27143_b6a921b4829f9a273a66bd6e0cbd29f4.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Anti-inflammatory Agents Suppress the Prostaglandin E2 Production and Migration Ability of Cholangiocarcinoma Cell Lines
Prostaglandin E2 (PGE2), one of the products catalyzed by cyclooxygenases (COXs), could actuate severalpathways implicated in chronic inflammation-related cancer, including apoptosis evasion, cell proliferation,migration and angiogenesis. We hypothesized that blocking of PGE2 production might be an effective strategy toattenuate the progression of cholangiocarcinoma (CCA). Thus, the aim of this study was to examine the effects oftwo anti-inflammatory agents, meloxicam, a selective COX-2 inhibitor, and xanthohumol, a natural plant extract,on PGE2 production and migration ability of human CCA cell lines. The results showed that 100 μM of meloxicamand 10 μM of xanthohumol suppressed the PGE2 level in the cultured media and wound-induced migration ofhuman CCA cell lines, M139 and M214. The present results revealed that meloxicam and xanthohumol havepotential to suppress PGE2 production and cell migration. These findings may offer alternative approaches forchemoprevention and therapy of CCA.
PGE2
cholangiocarcinoma
Meloxicam
xanthohumol
2012
12
01
47
51
https://journal.waocp.org/article_27144_e7f9fd8b482c05773107fa67df079d81.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Hypoxia Enhances Aggressiveness of Cholangiocarcinoma Cells
Hypoxia, a common feature of solid tumors, plays a significant role in determining tumor phenotype andtumor progression. In this study, using an in-house PCR-array, we investigated phenotypic changes anddifferentially expressed hypoxia related genes in the KKU-M213 CCA cell line, cultured under hypoxic (1% O2)condition. Trefoil factor-1 (TFF1), a disintegrin, and metalloprotease 12 (ADAM12), integrin-alpha 5 (ITGA5)and baculoviral IAP repeat-containing 5 (BIRC5/survivin), proteins involved with cell proliferation, metastasisand apoptosis resistance, were up-regulated whereas uridine 5’-monophosphate synthase (UMPS) and S100calcium binding protein P (S100P), involved with chemosensitivity and cell adhesion, were down-regulated.Growth arrest, apoptosis resistance to UV-irradiation and chemotherapeutic drugs (5- flourouracil, cisplatin,doxorubicin) as well as cell adhesion were thus significantly enhanced upon exposure to hypoxic condition. Thesefindings emphasize the significance of a hypoxic state in the induction of an aggressive phenotype and suggestthe potential of targeting hypoxia regulated genes to enhance the sensitivity of chemotherapeutic drug againstCCA.
Bile duct cancer
hypoxia
PCR-array-TFF1
BIRC5/survivin
2012
12
01
53
58
https://journal.waocp.org/article_27145_9dfbf7f01173f0a9bed0e95ceb44fb22.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Impaired Antioxidant Enzyme Activity and Increased DNA Repair Enzyme Expression in Hamster Liver Tissues Related to Cholangiocarcinoma Development
A possible mechanism of liver fluke (Opisthorchis viverrini; Ov) -associated cholangiocarcinoma (CCA) genesismay be imbalance in responses of antioxidant enzymes and/or DNA repair enzymes which are the consequenceof oxidative/nitrative stress, arising from inflammatory processes. This study aimed to investigate changes inthe expression patterns of antioxidant enzymes, including superoxide dismutase 2 (SOD2) and catalase (CAT),as well as their activities in Ov-associated hamster CCA tissues. Expression of DNA repair enzymes includingapurinic endonuclease (APE) and DNA polymerase beta (DNA pol β) was also investigated. Our resultsshowed that SOD2 and CAT levels were increased in CCA-induced liver hamster tissues at every time pointduring cholangiocarcinogenesis. However, once tumors were well established, activities of both enzymes weresignificantly decreased. Expression of APE and DNA pol β was increased in the acute phase of Ov infection andthis persisted until tumors developed. These findings suggest that a reduction in antioxidant enzymes and anincrease in DNA repair enzymes may contribute to DNA translesion-mediated CCA in liver fluke-associatedcholangiocarcinogenesis in the hamster model.
Opisthorchis viverrini
cholangiocarcinoma
Antioxidant enzymes
DNA repair enzymes
2012
12
01
59
64
https://journal.waocp.org/article_27146_ad7c2cd987bb6f13412a830f185432a2.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Expression Profiles of Oncomir miR-21 and Tumor Suppressor let-7a in the Progression of Opisthorchiasis-Associated Cholangiocarcinoma
Altered miRNA expression could be a determinant of cancer development and/or progression. We aimedto study the role of oncomir miR-21 and tumor suppressor let-7a in the genesis of Opisthorchiasis-associatedcholangiocarcinoma (CCA). The results showed that miR-21 was up-regulated while let-7a was down-regulatedduring cholangiocarcinogenesis in the hamster model and also in human CCA samples. The expression levelof miR-21 had an inverse correlation with the mRNA level of its target RECK, a metastasis suppressor, inhuman CCA. Knockdown of miR-21 of KKU100 CCA cells significantly increased the mRNA level of RECKand suppressed the wound-induced migration of CCA cells. Our data suggest that miR-21 is one key moleculeplaying crucial roles in the CCA growth and metastasis. Manipulation of miRNA expression offers a potentialavenue of CCA therapy.
miR-21
let-7a
RECK
Opisthorchis viverrini
cholangiocarcinoma
2012
12
01
65
69
https://journal.waocp.org/article_27147_1cea2f270d138b9e84775c3e55942bf2.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Overexpression of Claudin-4 in Cholangiocarcinoma Tissues and its Possible Role in Tumor Metastasis
Claudin-4 (CLDN4) is a tight junction protein that forms apical junctional complexes in epithelial andendothelial cellular sheets. Acting as a barrier and control of permeability are the general functions of tightjunction proteins contributing to tissue homeostasis, paracellular ion flux, and cell-cell contact. In this study,we immunohistochemically examined CLDN4 expression in liver fluke-associated cholangiocarcinomas (CCAs)with tissue microarrays. Regardless of the histological type and gross type of cancer, high expression of CLDN4was noted in precancerous hyperplastic/dysplastic biliary epithelia and CCA. To investigate functional roles ofCLDN4 in cancer progression, the effects of CLDN4 suppression by siRNA on cell proliferation, migration andinvasion were investigated in two CCA cell lines, KKU-M139 and KKU-M213. Suppression of CLDN4 expressiondid not alter cell proliferation but caused significant reduction of cell migration and invasion by both CCA celllines. Our results suggest that over-expressed CLDN4 may promote CCA expansion and metastasis.
Bile duct cancer
CLDN4
Proliferation
migration
Invasion
2012
12
01
71
76
https://journal.waocp.org/article_27148_8fa81ea6785995ab46259fd64ae82e2b.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Identification of Biliary Bile Acids in Patients with Benign Biliary Diseases, Hepatocellular Carcinoma and Cholangiocarcinoma
Bile acids are implicated as aetiological factors in many types of gastrointestinal tract cancer includingcholangiocarcinoma (CCA). Alterations in bile acid concentrations may affect the pathogenesis of these differenttypes of cancer. Our aim was to determine the bile acid profile in gallbladder bile from patients who underwentliver resection. Thirty-seven patients with cholangiocarcinoma, 5 with hepatocellular carcinoma, and 7 withbenign biliary diseases were studied. High pressure liquid chromatography was used to analyze conjugated andunconjugated bile acids. CCA patients with low (≤2 mg/dl) and high (>2 mg/dl) levels of total serum bilirubinhad significantly higher total bile acid and conjugated bile acid concentrations than the benign biliary diseasegroup. Markedly elevated levels of cholic and chenodeoxycholic acid were found in CCA cases with high levelsof total serum bilirubin. Concentrations of total bile acids and primary bile acid were correlated with serumcholesterol, bilirubin and ALP in CCA. Notably, correlation of the carcinoembryonic antigen, a tumor marker,was found with level of total bile acids and chenodeoxycholic acid. These findings suggest a different pattern ofbile acid concentration in cancer patients compared to patients with benign biliary diseases. Thus, accumulationof certain bile acids may be involved in carcinogenesis.
bile acids
cholangiocarcinoma
Hepatocellular carcinoma
2012
12
01
77
82
https://journal.waocp.org/article_27149_98493bfb2b4ee07838906bf1e86d0a3b.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Viral Hepatitis B, C Infection and Genotype Distributionamong Cholangiocarcinoma Patients in Northeast Thailand
The prevalence of HBV and HCV infection among 295 cholangiocarcinoma (CCA) patients in northeast Thailand was analyzed. Hepatitis B surface antigen (HBsAg) was detected in 8.8% (26/295 cases) and antibodies to HCV (anti-HCV) in 2.7% (8/295 cases) of CCA cases. Screening for HBV DNA was performed in 15 of 26 HBV seropositive cases and genotypes could be determined in all 15. HBV genotypes C and B were detected in 73.3% (11/15 cases) and 26.7% (4/15 cases), respectively. HCV RNA was detected in 87.5% (7/8 cases) of anti-HCV positive cases. Specifically, 57.1% (4/7 cases) were HCV genotype 1a and 42.9% (3/7 cases) were HCV genotype 3a. The prevalence of infection and genotype distribution of both HCV and HBV among CCA in northeast Thailand is comparable to that in the general population, suggesting that HCV and HBV infections are, if at all, not serious risk factors for CCA.
cholangiocarcinoma
HBV
HCV
northeast Thailand
2012
12
01
83
87
https://journal.waocp.org/article_27150_69557669353e4c28b875a759b193dcca.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Serial Analysis of Gene Expression Reveals Promising Therapeutic Targets for Liver Fluke-associated Cholangiocarcinoma
Cholangiocarcinoma (CCA) continues to be a serious health problem and is the most common fatalcancer in northeastern Thailand. Comprehensive gene expression analysis was here used to identify possibletherapeutic targets for CCA treatment. We assessed liver fluke-associated CCA tissue using serial analysis ofgene expression (SAGE) and compared the data to normal liver tissue as a part of the Cancer Genome AnatomyProject (CGAP). The analysis identified 509 differentially expressed genes. Of 142 up-regulated examples, weselected candidates including TMSB10, GAL3, VDR, CYPA and CD147 for further validation in CCA tissues byimmunohistochemistry. VDR, CYPA and CD147 were confirmed to be consistently overexpressed in the samplestested. The therapeutic and diagnostic potential of these genes warrants further investigation.
cholangiocarcinoma
Bile duct cancer
serial analysis of gene expression
SAGE
2012
12
01
89
93
https://journal.waocp.org/article_27151_a4f4bfc58f8cbe35855033fa04850156.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Aberrant Expression of CD44 in Bile Duct Cancer Correlates with Poor Prognosis
CCD44, a transmembrane glycoprotein receptor, plays significant roles in cell migration, differentiation, andsurvival signaling which are important for both normal and cancer cells. In this study, we examined the expressionof all isoforms of CD44 by immunohistochemistry in 3 cases of biliary cystadenoma, 15 cases of non-invasivecystadenocarcinoma (CAC) bile duct tumors, and 67 cases of the aggressive bile duct tumor, cholangiocarcinoma(CCA). Normal bile duct epithelia at different segments along the biliary tree did not express CD44. However,normal biliary cells of the large bile duct adjacent to tumor areas and dysplastic biliary cells in CCA tissues werepositive. CD44 was not expressed in cystadenomas and the majority of CACs. Two CAC cases with short survivaland the majority of CCA aberrantly expressed CD44. These observations suggest important roles for CD44 inthe early stage of carcinogenesis and progression of bile duct cancer. Regardless of the type of bile duct tumor,CAC or CCA patients with positive CD44 expression in biliary epithelia had significant shorter survival thanthose with negative CD44. Aberrant expression of CD44 in CAC or CCA tissues may indicate an unfavorablepatient outcome and may serve as a useful practical adjunct to conventional prognostic indicators for bile ductcancer.
CD44
isoform - variant - cholangiocarcinoma - prognosis
2012
12
01
95
99
https://journal.waocp.org/article_27152_b8c88cca2cc4eae1c614974af7ca2593.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Overexpression of O-GlcNAc-Transferase Associates with Aggressiveness of Mass-Forming Cholangiocarcinoma
O-GlcNAcylation, an important O-linked glycosylation of cellular glycoproteins with a single molecule ofN-acetylglucosamine (GlcNAc), is involved in regulation of many cellular processes. Alteration of O-GlcNAcylationis associated with the development and progression of many cancers. Here, we demonstrated aberrantO-GlcNAcylation in the cholangiocarcinoma (CCA) using immunohistochemistry of O-GlcNAc modified proteins(OGP), O-GlcNAc transferase (OGT) and N-acetylglucosaminidase (O-GlcNAcase or OGA). OGP expressionwas low in normal bile ducts corresponding with the low OGT and high OGA expression. In contrast, OGPwas strongly expressed in CCA tissues together with the up-regulation of OGT and down-regulation of OGA.Moreover, elevation of O-GlcNAcylation was associated with non-papillary type CCA and poor survival outcomeof CCA patients. Our study showed for the first time that O-GlcNAcylation is increased in CCA tissues and isassociated with a poor patient outcome. The OGT expression level could be a useful prognostic indicator andinhibition of O-GlcNAcylation might be a therapeutic target for CCA.
O-GlcNAcylation
O-linked β-N-acetylglucosaminyl transferase
N-acetylglucosaminidase
glycosylation
2012
12
01
101
105
https://journal.waocp.org/article_27153_c1ed4aa079225da4d304049e5bfd1939.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Serum Adhesion Molecule-1 (ICAM-1) as a Potential Prognostic Marker for Cholangiocarcinoma Patients
Cholangiocarcinoma (CCA) is a malignancy of bile ducts with a high incidence of invasion and metastasis.This disease is often detected in advanced stages because of the difficulties of early diagnosis, leading to a highmortality rate. However, biomarkers for early CCA detection are still lacking. In this study, to identify potentialbiomarker proteins, differential secretome analysis by the GeLC-MS/MS approach was applied with four CCAcell lines and a control immortalized cholangiocyte cell line. Among 78 up-regulated proteins, 53 including ICAM-1 were exclusively expressed in four CCA secretomes but not in MMNK1. Based on this result, we measuredICAM-1 levels in serum samples of CCA patients and healthy controls and found significantly higher values inCCA patients’ sera. Receiver operating characteristic curve analysis suggested that serum ICAM-1 level couldbe a discriminatory diagnostic marker for CCA and healthy controls (area under curve=0.829) with a sensitivityof 77% and a specificity of 70% at a cut off value of 167 ng/ml. Moreover, the serum ICAM-1 showed positivecorrelations with alkaline phosphatase and carcinoembryonic antigen levels. Comparison of ICAM-1 levels ofpaired pre- and post-operative sera of 12 cases revealed significant decrease after tumor resection. However,serum ICAM-1 levels were not significantly different between CCA and benign biliary diseases with mainlyinflammatory features.
cholangiocarcinoma
Secretome
adhesion molecule-1 (ICAM-1)
2012
12
01
107
114
https://journal.waocp.org/article_27154_4fb88794fcfa3883f8997a6f4203e34a.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Cytokines Released from Activated Human Macrophages Induce Epithelial Mesenchymal Transition Markers of Cholangiocarcinoma Cells
Stromal-epithelial interactions are important for carcinogenesis. Once cancerous lesions develop, a chronicallyinflamed tumor microenvironment promotes migration and invasion of tumor cells. Multiple immune cellpopulations are involved in inflammatory processes, including tumor-associated macrophages (TAMs) whichhave been proposed as major contributors to tumor progression. The epithelial-mesenchymal transition (EMT)is a process in which epithelial cells trans-differentiate and acquire an invasive mesenchymal phenotype. AsEMT represents a crucial step in disease progression, it is important to investigate the mechanisms regulatingthis step. We aimed to identify the profiles of cytokines produced by activated human macrophages and todemonstrate effects on the expression of EMT-related genes in human cholangiocarcinoma (CCA) cell lines. Ourresults showed that LPS-activated macrophages produced and secreted IL4, IL6, IL10, TNF-α and TGF-β1.After addition of macrophage conditioning media to CCA cells, expression of epithelial markers E-cadherinand CK-19 was significantly reduced, whereas the expression of mesenchymal markers, S100A4 and MMP9was strongly induced. Taken together, various cytokines secreted by activated macrophages could induce EMTby altering the expression of EMT-related genes in CCA.
Macrophages
macrophage-derived cytokines
epithelial mesenchymal transition
cholangiocarcinoma
2012
12
01
115
118
https://journal.waocp.org/article_27155_fe8ef95c9cd36414b7d077f9b58aff61.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Aberrant Glycosylation in Cholangiocarcinoma Demonstrated by Lectin-histochemistry
Cholangiocarcinoma (CCA) is an aggressive malignant tumor which is difficult to diagnose at an early stage.Because no reliable CCA specific markers are available at present, most patients are diagnosed after late clinicalpresentation. In many tumors, aberrant glycans participate in various steps of pathogenesis and progression. Inthis study, we investigated aberrant glycosylation in CCA tissues using lectin histochemistry to allow associationsof specific glycans with clinicopathological features of the patients to be investigated. For this purpose, 14 lectinsspecific to 5 main glycan structures were used for screening. Nine lectins showed positive staining in hepatocytesand stromal cells in liver tissues whereas three lectins, sWGA, SJA and UEA-I, had negative lectin bindingto hepatocytes and normal bile duct epithelia but exhibited positive staining with CCA. sWGA was selectedfor further evaluation of (β-D-GlcNAc)n-glycoconjugate expressions in 44 CCA tissues. We found that sWGAspecificglycans were aberrantly expressed along with CCA development and the level of expression variedwith histological types. It was highly expressed in papillary and well-differentiated types but was significantlyreduced in poorly-differentiated lesions. Specific associations of sWGA-specific glycoconjugate expression withclinicopathological features or overall survival of patients were not apparent in this cohort study.
bile duct
GlcNAc
lectin
sWGA
cholangiocarcinoma
2012
12
01
119
124
https://journal.waocp.org/article_27156_ae49af58c935f3492bf2e1293a3f7678.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
High Expression of ABCC1 Indicates Poor Prognosis in Intrahepatic Cholangiocarcinoma
Intrahepatic cholangiocarcinoma (ICC) is a serious health problem in Thailand. To reach a cure, radicalresection is the gold standard but most patients are not candidates because of delayed first presentation.Palliative surgery and/or combined chemotherapy are alternatives; however, outcomes are still unsatisfactory.A low response to multiple anticancer drugs might be due to a multidrug resistance (MDR) phenotype of ICC.In this study, we investigated the expression profile of selected adenosine triphosphate binding cassette (ABC)transporter superfamily members, the major contributors to cancer MDR, and determined the clinical significanceof certain examples in ICC. Expression of 9 ABC transporters; ABCB1, ABCB11, ABCC1, ABCC2, ABCC3,ABCC4, ABCC6, ABCC11 and ABCG2, was determined in 55 ICC tissues using real-time RT-PCR. The resultsshowed that ABCC1, ABCC2, ABCC3 and ABCC4 were differentially expressed in ICC tissues. Only ABCC1expression was significantly higher in ICC tissues than those of the corresponding non-tumor tissues (P<0.001),significantly correlating with shortened overall survival time (P<0.05). Multivariate analysis indicated thatexpression is an independent clinicopathological factor (adjusted HR=5.689; 95%CI=1.042-31.076; P<0.05).These results suggested that ABCC1 is a candidate prognostic marker for ICC.
Bile duct cancer
Intrahepatic cholangiocarcinoma
ICC
ABC transporter expression
ABCC1
2012
12
01
125
130
https://journal.waocp.org/article_27157_b9465981a08186e25fd0ca3d925ab89f.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
NQO1 Expression Correlates with Cholangiocarcinoma Prognosis
Cholangiocarcinoma (CCA) is a rare type of liver cancer with a very poor prognosis. The prevalence of CCAis markedly variable with the highest incidence in the northeast Thailand, followed by other parts of SoutheastAsia and China. Currently, there is still no reliable biomarker for diagnosis or treatment. NADPH-quinoneoxidoreductase 1 (NQO1) is a xenobiotic metabolizing enzyme detoxifying chemical stressors and antioxidants,thereby providing cytoprotection in normal tissues. However, NQO1 is over-expressed in some cancers, suggestingroles in carcinogenesis and tumor progression. In this study, we examined NQO1 activity in surgical specimensfrom CCA patients and found much higher values than in the adjacent normal tissues. Immunohistochemicalanalysis revealed strong staining in tumor epithelial elements, whereas the non-tumor bile ducts and liverparenchyma were weakly stained. NQO1 mRNA expression in tumor tissues was widely varied among 43 patients.A significant association was observed between high level of NQO1 expression and short overall survival time bythe Cox proportional hazard ratio of 2.40, p<0.05. By histological classification, non-papillary adenocarcinomawas an independent predictor for poor prognosis with the hazard ratio of 2.79, p<0.05. NQO1 expression mayserve as a prognostic biomarker for the CCA.
NADPH-quinone oxidoreductase 1-drug metabolizing enzyme antioxidant-cytoprotection
2012
12
01
131
136
https://journal.waocp.org/article_27158_4006da21b588356aebef1d797bfff4f7.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Possible Involvement of Cyclophilin A Processing in Fumagillin-Induced Suppression of Cholangiocarcinoma Cell Proliferation
Methionine aminopeptidase 2 (MetAP2), a proteolytic enzyme that removes the N-terminal methioninefrom newly synthesized cellular proteins, plays roles in the development of various cancers and has been foundto be over-expressed in cholangiocarcinoma (CCA). Fumagillin, a specific MetAP2 inhibitor, suppresses CCAcell proliferation. In order to determine the molecular mechanisms involved in the suppression of CCA cellproliferation caused by fumagillin, proteomic analysis was performed on fumagillin-treated CCA cells. Proteinsaffected by fumagillin were analyzed using 2D gel electrophoresis and matrix-assisted laser desorption ionizationtimeof flight tandem mass spectrometry (MALDI-TOF/TOF). The results showed that the processed form ofcyclophilin A (CypA) was greatly decreased in parallel with the suppression of CCA cell proliferation. Theseresults suggest that CypA is possibly a protein substrate of MetAP2 cleavage. Removal of N-terminal methionineby MetAP2 may be essential for proper function of CypA in CCA cell proliferation. MetAP2 and CypA maythus serve as potential therapeutic targets for CCA treatment.
cholangiocarcinoma
Bile duct cancer
methionine aminopeptidase 2
fumagillin
cyclophilin A
2012
12
01
137
141
https://journal.waocp.org/article_27159_4be1ca4aabe627652beb82d9f912b1ec.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Suppression of PRKAR1A Expression Enhances Antiproliferative and Apoptotic Effects of Protein Kinase Inhibitors and Chemotherapeutic Drugs on Cholangiocarcinoma Cells
Suppression of protein kinase A regulatory subunit 1 alpha (PRKAR1A) has been proven to inhibitcholangiocarcinoma (CCA) cell growth and enhance apoptosis. In the present study, we aimed to determinesynergistic and/or additive effects of chemotherapeutic agents, including protein kinase inhibitors (i.e. sorafenib,sunitinib, gefitinib, Met inhibitor) and conventional chemotherapeutic drugs (i.e. 5-fluorouracil, doxorubicin,paclitaxel, gemcitabine), in PRKARIA knockdown CCA cell lines. The results revealed that PRKAR1A suppressedCCA cell lines demonstrated enhanced sensistivity to some chemotherapeutic drugs when compared to controlcells. Moreover, PRKAR1A knockdown in combination with either sorafenib or 5-fluorouracil increased apoptoticeffects on CCA cell lines. Therefore, selective inhibition of PRKAR1A appears to enhance the growth inhibitoryeffects of chemotherapeutic drugs as well as induce apoptotic cell death. Our findings suggest that additionalsuppression of PRKAR1A expression may increase the efficacy of conventional CCA chemotherapeutic treatment.Clinical studies in CCA patients now need to be conducted.
cholangiocarcinoma
PRKAR1A knockdown
kinase inhibitors
chemotherapeutic drugs
2012
12
01
143
147
https://journal.waocp.org/article_27160_493e75d18d29cede0939d7ed5eef38de.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Cepharanthine Suppresses Metastatic Potential of Human Cholangiocarcinoma Cell Lines
Cholangiocarcinoma (CCA) is a highly metastatic tumor with poor responses to traditional chemotherapeuticagents. We have focused on new drugs which can exert effects either alone or in combination with available agentsfor a better treatment of CCA and recently reported efficacy of cepharanthine (CEP), a natural biscoclaurinealkaloid extract with anti-proliferative activity against human CCA cell lines. CEP treatment effectivelysuppressed tumor growth in CCA-inoculated mice without serious side-effects and also increased cell apoptosisin primary histocultures of CCA patient tissues, suggesting therapeutic potential of CEP against human CCA.In the present study, we further showed anti-metastatic effects of CEP on migration and invasion of human CCAcell lines. CEP at 10 μg/mL effectively suppressed migration activity of KKU-M213 and KKU-M214 as shown bywound healing and Boyden chamber assays. Similar suppressive effects were observed in invasion assays. Themolecular mechanism underlying CEP actions on cell motility and invasion could be shown to involve suppressionof ICAM-1 and MMP-2. Our results suggest CEP as a potential therapeutic agent for treating metastatic CCA.
NF-KB
Metastasis
migration
Invasion
Bile duct cancer
2012
12
01
149
154
https://journal.waocp.org/article_27161_477ce7121207f82a828ad0890be4b3d3.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
TNP-470, A Methionine Aminopeptidase-2 Inhibitor, Inhibits Cell Proliferation, Migration and Invasion of Human Cholangiocarcinoma Cells In Vitro
Methionine aminopeptidase-2 (MetAP2) is over-expressed in several cancers, including the cholangiocarcinoma(CCA). We reported previously suppressive effects of fumagillin, a MetAP2 inhibitor, on growth of CCA cell lines.In the present study, we evaluated the anti-proliferative and anti-invasive activities of TNP-470, a fumagillinanalogue with higher MetAP2 inhibitory activity, on CCA cell lines (KKU-M213 and KKU-M214). TNP-470significantly inhibited growth of both lines in a dose and time dependent fashion. Moreover, a sub-toxic dose ofTNP-470 significantly reduced migration and invasion of CCA cells. Exploration of the molecular mechanismsby which TNP-470 inhibited growth and metastasis of CCA cell lines demonstrated expression of c-MYC, MMP2and MMP9 to be decreased in TNP-470 treated cells. These results suggest that TNP-470 could be a potentialtherapeutic agent for CCA.
TNP-470
MetAP
MetAP2
MMP9
Metastasis
angiogenesis inhibitor
2012
12
01
155
160
https://journal.waocp.org/article_27162_c99b3dc4273261d4231d0c85360d99b6.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Evaluation of Efficacy, Safety and Tolerability of High Dose-Intermittent Calcitriol Supplementation to Advanced Intrahepatic Cholangiocarcinoma Patients - A Pilot Study
Antitumor activity (growth suppression) of vitamin D has been demonstrated using cholangiocarcinoma(CCA) cell lines, CCA cell-grafted animal models, and human CCA tissue cultures. The present study aimed todetermine the toxicity and tolerability of intermittent-high dose calcitriol in advanced inoperable intrahepaticCCA patients and to evaluate the therapeutic efficacy of combinations of calcitriol and 5-fluorouracil-basedchemotherapeutic drugs. The patients were divided into 3 groups: the first (n=2) received intermittent-highdose oral calcitriol 12 μg/day for 3 days, i.e. Monday-Wednesday, per week up to 3 months. The treatment didnot cause any serious adverse events, except hypercalcemia grade I, once in 72 administrations. The secondgroup (n=3) received chemotherapeutic drugs (5-fluorouracil, Mitomycin C and Leucovorin) for 3 cycles, onepatient showing a partial response. The third group (n=4) received high dose calcitriol in combination withchemotherapeutic-drugs. All 4 patients encountered serious adverse events and two of them were withdrawnafter the first drug cycle. This pilot study suggests that, although high dose-intermittent calcitriol appeared tobe safe and tolerated well in advanced intrahepatic CCA patients, co-administration with 5-fluorouracil-basedchemotherapeutic drugs caused unexpected potentiation of their toxicity. Adjustment of the doses of both drugs isrequired to avoid such toxicity and to optimize therapeutic efficacy of anticancer drugs when they were combinedwith high dose-intermittent calcitriol. USA Clinical Trial : NCT01039181.
Vitamin D
Clinical trial
treatment
5-fluorouracil
2012
12
01
161
167
https://journal.waocp.org/article_27163_a041a1e00186b838b54c9abb6d50ac16.pdf
Asian Pacific Journal of Cancer Prevention
Asian Pac J Cancer Prev
1513-7368
1513-7368
2012
13
KKSuppl
Evaluation of Postoperative Adjuvant Chemotherapy for Intrahepatic Cholangiocarcinoma Patients undergoing R1 and R2 Resections
Surgical resection is the gold standard treatment and is considered the only potential cure for cholangiocarcinoma(CCA). However, most of the patients present at a late stage of disease and positive margins are frequentlyencountered. Therefore, adjuvant therapeutic modalities, such as chemotherapy and/or radiotherapy are neededto improve the survival time of CCA patients. In this study, we analyzed retrospectively the clinical features,overall survival and efficacy with postoperative adjuvant chemotherapy for 171 intrahepatic CCA patients.All those with histologically proved intrahepatic CCA diagnosed during 1998-2002, at Srinagarind Hospital,Faculty of Medicine, Khon Kean University, Thailand, were included in this study. All patients were consideredto have resectable tumors with curative intent, 114 patients received postoperative adjuvant chemotherapywith 5-fluorouracil/mitomycin C, of which only 54 patients were given the full 6 cycle treatment. Mass formingtype CCA was the major type found in our series. The predictive clinicopathological factors which influencedan unfavorable outcome were tumor size >4 cm, multiple masses, mass forming and periductal gross type,histology with poor differentiation, involvement of serosa, vasculature or diaphragm, advanced tumor stageand positive surgical margin. On the other hand, R0 resection, skeletonization of hepatoduodenal ligaments andcomplete postoperative adjuvant chemotherapy were predictive of a favorable outcome. Multivariate analysisCox proportional hazards models revealed that sex, tumor size, serosa involvement, surgical margin status,skeletonization and postoperative adjuvant chemotherapy were independently associated with long term survivalpost-surgery. Regardless of the surgical margin status, patients who received complete postoperative adjuvantchemotherapy had a significant survival advantage.
bile duct
survival
Prognosis
Adjuvant chemotherapy
5-fluorouracil
treatment
2012
12
01
169
174
https://journal.waocp.org/article_27164_e80377aceb6179454a95d457e1a5054c.pdf